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  3. PubMed:22908190

PubMed: 22908190

Title
The ubiquitin-proteasome system and the autophagic-lysosomal system in Alzheimer disease.
Journal
Cold Spring Harbor perspectives in medicine
Volume
2
Issue
None
Pages
None
Date
2012-08-01
Authors
Ihara Y | Morishima-Kawashima M | Nixon R

Evidence ad31e2ea05
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It has been reported that tau is degraded by several major cellular degradation systems, including calpain, caspases, lysosomes, and proteasomes.

a(GO:lysosome) increases deg(p(HGNC:MAPT)) View Subject | View Object

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complex(GO:"proteasome complex") increases deg(p(HGNC:MAPT)) View Subject | View Object

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p(FPLX:CAPN) increases deg(p(HGNC:MAPT)) View Subject | View Object

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p(FPLX:Caspase) increases deg(p(HGNC:MAPT)) View Subject | View Object

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Evidence a4fccf9acf
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By up-regulating endocytosis, high dietary LDL-cholesterol and overexpression of its receptor ApoE (particularly ApoE 14) elevate bCTF levels and increase delivery of Ab1–42 to lysosomes in cellular model systems (Ji et al. 2006; Cossec et al. 2010).

tloc(a(CHEBI:"amyloid-beta polypeptide 42"), fromLoc(GO:cytosol), toLoc(GO:lysosome)) positiveCorrelation bp(GO:endocytosis) View Subject | View Object

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tloc(a(CHEBI:"amyloid-beta polypeptide 42"), fromLoc(GO:cytosol), toLoc(GO:lysosome)) positiveCorrelation g(HBP:"APOE e4") View Subject | View Object

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tloc(a(CHEBI:"amyloid-beta polypeptide 42"), fromLoc(GO:cytosol), toLoc(GO:lysosome)) positiveCorrelation a(CHEBI:"low-density lipoprotein cholesterol") View Subject | View Object

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a(CHEBI:"low-density lipoprotein cholesterol") positiveCorrelation p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") View Subject | View Object

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a(CHEBI:"low-density lipoprotein cholesterol") positiveCorrelation tloc(a(CHEBI:"amyloid-beta polypeptide 42"), fromLoc(GO:cytosol), toLoc(GO:lysosome)) View Subject | View Object

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bp(GO:endocytosis) positiveCorrelation p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") View Subject | View Object

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bp(GO:endocytosis) positiveCorrelation tloc(a(CHEBI:"amyloid-beta polypeptide 42"), fromLoc(GO:cytosol), toLoc(GO:lysosome)) View Subject | View Object

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g(HBP:"APOE e4") positiveCorrelation p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") View Subject | View Object

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g(HBP:"APOE e4") positiveCorrelation tloc(a(CHEBI:"amyloid-beta polypeptide 42"), fromLoc(GO:cytosol), toLoc(GO:lysosome)) View Subject | View Object

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p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") positiveCorrelation g(HBP:"APOE e4") View Subject | View Object

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p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") positiveCorrelation a(CHEBI:"low-density lipoprotein cholesterol") View Subject | View Object

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p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") positiveCorrelation bp(GO:endocytosis) View Subject | View Object

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Evidence 8a0a861c9b
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Consistent with these findings, strong overexpression of human Ab42, but not Ab40, in Drosophila neurons induces age-related accumulation of Ab in autolysosomes and neurotoxicity (Ling et al. 2009).

a(CHEBI:"amyloid-beta polypeptide 42") positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

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MeSH
Neurons

a(CHEBI:"amyloid-beta polypeptide 42") positiveCorrelation path(HBP:neurotoxicity) View Subject | View Object

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MeSH
Neurons

a(CHEBI:"amyloid-beta") positiveCorrelation a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

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MeSH
Neurons

path(HBP:neurotoxicity) positiveCorrelation a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

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MeSH
Neurons

Evidence a9dd0caa89
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Ab42-induced neurotoxicity is further enhanced by autophagy activation and is partially rescued by autophagy inhibition.

a(CHEBI:"amyloid-beta polypeptide 42") increases path(HBP:neurotoxicity) View Subject | View Object

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bp(GO:autophagy) increases path(HBP:neurotoxicity) View Subject | View Object

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Evidence e3eff1b319
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Moreover, administration of UCH-L1 can reverse the amyloid b-protein–induced synaptic dysfunction and memory loss in transgenic mice overexpressing APP and PS1 (Gong et al. 2006).

a(CHEBI:"amyloid-beta") decreases act(a(GO:synapse)) View Subject | View Object

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a(CHEBI:"amyloid-beta") decreases bp(GO:memory) View Subject | View Object

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p(HGNC:UCHL1) increases act(a(GO:synapse)) View Subject | View Object

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p(HGNC:UCHL1) increases bp(GO:memory) View Subject | View Object

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Evidence e62e60806e
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Thus, the accumulation of tau and of Ab, forming the two major protein lesions of AD, impairs proteasome activity in vivo.

a(CHEBI:"amyloid-beta") negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

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MeSH
Alzheimer Disease

act(complex(GO:"proteasome complex")) negativeCorrelation p(HGNC:MAPT) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

act(complex(GO:"proteasome complex")) negativeCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT) negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

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MeSH
Alzheimer Disease

Evidence e87d5d6ca5
JSON

Endocytic pathway up-regulation in AD stemming in part from pathological rab 5 activation generates higher levels of Ab (Mathews et al. 2002; Grbovic et al. 2003) that must be cleared in part by lysosomes.

a(CHEBI:"amyloid-beta") positiveCorrelation bp(GO:endocytosis) View Subject | View Object

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bp(GO:"lysosomal protein catabolic process") increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

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bp(GO:endocytosis) positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

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act(p(HGNC:RAB5A)) increases bp(GO:endocytosis) View Subject | View Object

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act(p(HGNC:RAB5A)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

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Evidence 66f828931b
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Pathological rab5 activation, which in Down syndrome is dependent on bCTF generation (Jiang et al. 2010), can up-regulate endocytosis in a manner functionally equivalent to the elevated endocytosis associated with increased synaptic activity, which is considered a source of Ab generation (Cirrito et al. 2008).

a(CHEBI:"amyloid-beta") positiveCorrelation bp(GO:endocytosis) View Subject | View Object

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MeSH
Down Syndrome

act(a(GO:synapse)) positiveCorrelation bp(GO:endocytosis) View Subject | View Object

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MeSH
Down Syndrome

bp(GO:endocytosis) positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

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MeSH
Down Syndrome

bp(GO:endocytosis) positiveCorrelation act(a(GO:synapse)) View Subject | View Object

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MeSH
Down Syndrome

p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") increases act(p(HGNC:RAB5A)) View Subject | View Object

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MeSH
Down Syndrome

act(p(HGNC:RAB5A)) increases bp(GO:endocytosis) View Subject | View Object

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MeSH
Down Syndrome

Evidence 2679943d5f
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Induction of autophagy is generally controlled by the mTOR kinase (mammalian Target of Rapamycin), which is regulated by growth factors (especially insulin) and nutrient levels.

a(CHEBI:"insulin (human)") regulates p(HGNC:MTOR) View Subject | View Object

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bp(GO:"response to nutrient") regulates p(HGNC:MTOR) View Subject | View Object

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p(HGNC:MTOR) regulates bp(GO:autophagy) View Subject | View Object

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Evidence fde0ed8feb
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High dietary LDL-cholesterol and overexpression of its receptor ApoE (particularly ApoE 14) elevate bCTF levels (Ji et al. 2006; Cossec et al. 2010), and these levels are also elevated in NPC, DS, and AD, particularly in early-onset forms of AD caused by certain mutations of APP.

a(CHEBI:"low-density lipoprotein cholesterol") positiveCorrelation p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") View Subject | View Object

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g(HBP:"APOE e4") positiveCorrelation p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") View Subject | View Object

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p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") positiveCorrelation g(HBP:"APOE e4") View Subject | View Object

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p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") positiveCorrelation a(CHEBI:"low-density lipoprotein cholesterol") View Subject | View Object

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Evidence 3ad21a5114
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In this regard, elevated bCTF levels induced by APP overexpression, elevated dietary cholesterol, or overexpression of its receptor ApoE (particularly ApoE 14) can upregulate endocytosis and enlarge endosomes (Laifenfeld et al. 2007; Chen et al. 2010; Cossec et al. 2010), leading to impaired endosome retrograde transport (S Kim and RA Nixon, unpubl.).

a(CHEBI:cholesterol) positiveCorrelation p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") View Subject | View Object

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a(CHEBI:cholesterol) positiveCorrelation bp(GO:endocytosis) View Subject | View Object

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a(CHEBI:cholesterol) increases a(GO:endosome) View Subject | View Object

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bp(GO:endocytosis) positiveCorrelation p(HGNC:APP) View Subject | View Object

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bp(GO:endocytosis) positiveCorrelation g(HBP:"APOE e4") View Subject | View Object

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bp(GO:endocytosis) positiveCorrelation a(CHEBI:cholesterol) View Subject | View Object

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p(HGNC:APP) positiveCorrelation p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") View Subject | View Object

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p(HGNC:APP) positiveCorrelation bp(GO:endocytosis) View Subject | View Object

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p(HGNC:APP) increases a(GO:endosome) View Subject | View Object

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g(HBP:"APOE e4") positiveCorrelation p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") View Subject | View Object

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g(HBP:"APOE e4") positiveCorrelation bp(GO:endocytosis) View Subject | View Object

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g(HBP:"APOE e4") increases a(GO:endosome) View Subject | View Object

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p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") positiveCorrelation g(HBP:"APOE e4") View Subject | View Object

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p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") positiveCorrelation p(HGNC:APP) View Subject | View Object

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p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") positiveCorrelation a(CHEBI:cholesterol) View Subject | View Object

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Evidence 71ecd92bb9
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Bilateral injection of lactacystin, a specific proteasome inhibitor, into the CA1 region of the rat hippocampus blocks long-term memory formation (Lopez-Salon et al. 2001

a(CHEBI:lactacystin) decreases bp(GO:"long-term memory") View Subject | View Object

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MeSH
CA1 Region, Hippocampal

Evidence 29de73c14d
JSON

It is this abnormal rab5 activation that causes protein and lipid accumulation in endosomes, slowed lysosomal degradation of endocytic cargoes,endosome swelling (Cataldo et al. 2008), and disrupted retrograde transport of endosomes (S Kim and RA Nixon, unpubl.).

a(CHEBI:lipid) positiveCorrelation act(p(HGNC:RAB5A)) View Subject | View Object

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a(MESH:Proteins) positiveCorrelation act(p(HGNC:RAB5A)) View Subject | View Object

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bp(GO:"lysosomal protein catabolic process") negativeCorrelation act(p(HGNC:RAB5A)) View Subject | View Object

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act(p(HGNC:RAB5A)) positiveCorrelation a(MESH:Proteins) View Subject | View Object

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act(p(HGNC:RAB5A)) positiveCorrelation a(CHEBI:lipid) View Subject | View Object

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act(p(HGNC:RAB5A)) negativeCorrelation bp(GO:"lysosomal protein catabolic process") View Subject | View Object

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Evidence 4d9d253c06
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Accelerated endocytosis also increases protein and lipid accumulation in endosomes and slows lysosomal degradation of endocytic cargoes (Cataldo et al. 2008), leading to lysosomal instability and neurodegeneration, as discussed below.

a(CHEBI:lipid) positiveCorrelation bp(GO:endocytosis) View Subject | View Object

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MeSH
Endosomes

a(MESH:Proteins) positiveCorrelation bp(GO:endocytosis) View Subject | View Object

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MeSH
Endosomes

bp(GO:"lysosomal protein catabolic process") negativeCorrelation bp(GO:endocytosis) View Subject | View Object

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MeSH
Endosomes

bp(GO:"lysosomal protein catabolic process") decreases path(HBP:Neurodegeneration) View Subject | View Object

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MeSH
Endosomes

bp(GO:endocytosis) positiveCorrelation a(MESH:Proteins) View Subject | View Object

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MeSH
Endosomes

bp(GO:endocytosis) positiveCorrelation a(CHEBI:lipid) View Subject | View Object

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MeSH
Endosomes

bp(GO:endocytosis) negativeCorrelation bp(GO:"lysosomal protein catabolic process") View Subject | View Object

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MeSH
Endosomes

Evidence e685fc001b
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Chronic low-level stimulation of autophagy through peripheral administration of rapamycin or other agents (Tian et al. 2011), or enhancing lysosomal proteolysis selectively (Sun et al. 2008; Yang et al. 2011), can markedly diminish Ab levels and amyloid load in APP transgenic mice, underscoring the importance of lysosomal clearance of Ab.

a(CHEBI:sirolimus) increases bp(GO:autophagy) View Subject | View Object

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bp(GO:"lysosomal protein catabolic process") increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

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bp(GO:autophagy) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

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Evidence ead9b64755
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Consistent with these findings, rapamycin induction of autophagy reduces tau pathology in the triple transgenic AD-mouse model (Caccamo et al. 2010), whereas in other models, autophagic–lysosomal dysfunction amplifies tau pathology and tau neurotoxicity (Hamano et al. 2008; Khurana et al. 2010).

a(CHEBI:sirolimus) increases bp(GO:autophagy) View Subject | View Object

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a(CHEBI:sirolimus) decreases path(MESH:Tauopathies) View Subject | View Object

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bp(GO:autophagy) decreases path(MESH:Tauopathies) View Subject | View Object

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bp(GO:autophagy) decreases path(HBP:neurotoxicity) View Subject | View Object

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Evidence c82711f657
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Peripheral administration of rapamycin to strongly stimulate autophagy substantially reduces amyloid deposition and tau pathology in both APPand triple transgenic mouse models of AD pathology (Caccamo et al. 2010; Spilman et al. 2010; Tian et al. 2011)

a(CHEBI:sirolimus) decreases path(MESH:Tauopathies) View Subject | View Object

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a(CHEBI:sirolimus) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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Evidence 4dd3d5f2af
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We soon found that DF2 strongly stained cortical and brain stem Lewy bodies in brain sections from “diffuse Lewy body disease” (Kuzuhara et al. 1988), as originally described by Kenji Kosaka (1978), who proposed that some elderly subjects dying with dementia had many cortical Lewy bodies

a(GO:"Lewy body") association a(MESH:Ubiquitin) View Subject | View Object

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MeSH
Brain Stem
MeSH
Cerebral Cortex
MeSH
Lewy Body Disease

a(GO:"Lewy body") positiveCorrelation path(MESH:Dementia) View Subject | View Object

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MeSH
Brain Stem
MeSH
Cerebral Cortex
MeSH
Lewy Body Disease

a(MESH:Ubiquitin) association a(GO:"Lewy body") View Subject | View Object

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Brain Stem
MeSH
Cerebral Cortex
MeSH
Lewy Body Disease

path(MESH:Dementia) positiveCorrelation a(GO:"Lewy body") View Subject | View Object

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MeSH
Brain Stem
MeSH
Cerebral Cortex
MeSH
Lewy Body Disease

Evidence c1f84436ee
JSON

The DF2 immunoreactivity of Lewy bodies led us to search for similar DF2-positive inclusions, and we found that Lewy-like bodies in motor neurons in amyotrophic lateral sclerosis (ALS; Murayama et al. 1990a) and Pick bodies in Pick’s disease (Murayama et al. 1990b) were strongly reactive; the latter stained also for tau, whereas the former stained neither for tau nor a-synuclein.

a(GO:"Lewy body") association a(MESH:Ubiquitin) View Subject | View Object

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MeSH
Motor Neurons
MeSH
Amyotrophic Lateral Sclerosis

a(GO:"Lewy body") association p(HGNC:MAPT) View Subject | View Object

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MeSH
Motor Neurons
MeSH
Amyotrophic Lateral Sclerosis

a(GO:"Pick body") association p(HGNC:MAPT) View Subject | View Object

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MeSH
Niemann-Pick Diseases

a(GO:"Pick body") association a(MESH:Ubiquitin) View Subject | View Object

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MeSH
Niemann-Pick Diseases

a(MESH:Ubiquitin) association a(GO:"Lewy body") View Subject | View Object

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MeSH
Motor Neurons
MeSH
Amyotrophic Lateral Sclerosis

a(MESH:Ubiquitin) association a(GO:"Pick body") View Subject | View Object

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MeSH
Niemann-Pick Diseases

p(HGNC:MAPT) association a(GO:"Lewy body") View Subject | View Object

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MeSH
Motor Neurons
MeSH
Amyotrophic Lateral Sclerosis

p(HGNC:MAPT) association a(GO:"Pick body") View Subject | View Object

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MeSH
Niemann-Pick Diseases

Evidence b3c02a0659
JSON

In this dementia, Lewy bodies are abundant in cortical neurons, especially in the cingulate gyrus, in addition to their presence in the substantia nigra and locus ceruleus, their prototypical loci in Parkinson’s disease.

a(GO:"Lewy body") positiveCorrelation path(MESH:Dementia) View Subject | View Object

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MeSH
Cerebral Cortex
MeSH
Gyrus Cinguli
MeSH
Locus Coeruleus
MeSH
Neurons
MeSH
Substantia Nigra
MeSH
Parkinson Disease

path(MESH:Dementia) positiveCorrelation a(GO:"Lewy body") View Subject | View Object

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MeSH
Cerebral Cortex
MeSH
Gyrus Cinguli
MeSH
Locus Coeruleus
MeSH
Neurons
MeSH
Substantia Nigra
MeSH
Parkinson Disease

Evidence 5ad9ed995b
JSON

Polyclonal antibodies to the classical paired helical filaments (PHFs) found in the neurofibrillary tangles and dystrophic neurites of AD were first raised in about 1982, allowing exploration of the component(s) of PHFs using immunochemical approaches (Ihara et al. 1983)

a(GO:"neurofibrillary tangle") association a(HBP:"paired helical filaments") View Subject | View Object

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MeSH
Alzheimer Disease

a(HBP:"dystrophic neurite") association a(HBP:"paired helical filaments") View Subject | View Object

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MeSH
Alzheimer Disease

a(HBP:"paired helical filaments") association a(GO:"neurofibrillary tangle") View Subject | View Object

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MeSH
Alzheimer Disease

a(HBP:"paired helical filaments") association a(HBP:"dystrophic neurite") View Subject | View Object

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MeSH
Alzheimer Disease

Evidence 681a58c35a
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In AD cortical sections, we observed that NFTs and dystrophic neurites (Fig. 1) and, unexpectedly, granulovacuolar changes (Fig. 1, inset) were intensely immunolabeled by the DF2 monoclonal. When mild fixation conditions were used, innumerable neuropil threads were also detected.

a(GO:"neurofibrillary tangle") association a(MESH:Ubiquitin) View Subject | View Object

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MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

a(HBP:"dystrophic neurite") association a(MESH:Ubiquitin) View Subject | View Object

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MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

a(MESH:"Neuropil Threads") association a(MESH:Ubiquitin) View Subject | View Object

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MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

a(MESH:Ubiquitin) association a(GO:"neurofibrillary tangle") View Subject | View Object

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MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

a(MESH:Ubiquitin) association a(HBP:"dystrophic neurite") View Subject | View Object

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MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

a(MESH:Ubiquitin) association path(HBP:"granulovacuolar degeneration") View Subject | View Object

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MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

a(MESH:Ubiquitin) association a(MESH:"Neuropil Threads") View Subject | View Object

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MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

path(HBP:"granulovacuolar degeneration") association a(MESH:Ubiquitin) View Subject | View Object

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MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

Evidence 3bcc381ee5
JSON

That is, in areas where NFTs formed abundantly, including hippocampus and parahippocampal gyrus and superior and middle temporal gyri, proteasome activity (as assessed by chymortrypsinlike and postglutamyl peptidases) appeared to be most affected, whereas occipital gyri and cerebellum, which often have few or no NFTs, were least affected (Keller et al. 2000).

a(GO:"neurofibrillary tangle") negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

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MeSH
Hippocampus
MeSH
Parahippocampal Gyrus
MeSH
Temporal Lobe

act(complex(GO:"proteasome complex")) negativeCorrelation a(GO:"neurofibrillary tangle") View Subject | View Object

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MeSH
Hippocampus
MeSH
Parahippocampal Gyrus
MeSH
Temporal Lobe

Evidence 3780a2a1dc
JSON

A proteomic analysis has shown down-regulation and oxidative modification of UCH-L1 in the AD brain, and the levels of soluble UCH-L1 were inversely proportional to the number of NFTs (Choi et al. 2004).

a(GO:"neurofibrillary tangle") negativeCorrelation p(HGNC:UCHL1, pmod(GO:"protein oxidation")) View Subject | View Object

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MeSH
Alzheimer Disease

p(HGNC:UCHL1, pmod(GO:"protein oxidation")) negativeCorrelation a(GO:"neurofibrillary tangle") View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

Evidence 5b2c4ca693
JSON

For example, immunocytochemistry showing the presence of K63- linked polyubiquitin in a fraction of the NFTs in AD cortex (Paine et al. 2009) suggests an active involvement of autophagy in the mechanism of AD.

a(GO:"neurofibrillary tangle") association bp(GO:"protein K63-linked ubiquitination") View Subject | View Object

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MeSH
Alzheimer Disease

bp(GO:"protein K63-linked ubiquitination") association a(GO:"neurofibrillary tangle") View Subject | View Object

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MeSH
Alzheimer Disease

bp(GO:autophagy) association path(MESH:"Alzheimer Disease") View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") association bp(GO:autophagy) View Subject | View Object

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MeSH
Alzheimer Disease

Evidence 0975e951cb
JSON

Neurofibrillary tangles composed of tau proteins in a hyperphosphorylated state are rarely observed in abundance except in AD and a limited number of aging-related tauopathies.

a(GO:"neurofibrillary tangle") association p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

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p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) association a(GO:"neurofibrillary tangle") View Subject | View Object

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Evidence 2191f91686
JSON

AV accumulations are not specific to the degenerative phenomena of AD; however, in AD brain, the extensive numbers of dystrophic neurites (Masliah et al. 1993; Schmidt et al. 1994), their characteristic marked distension, and the fact that they are predominantly filled with AVs distinguish the pattern and magnitude of this pathology from that of other aging-related neurodegenerative diseases (Benzing et al. 1993).

a(GO:autophagosome) association a(HBP:"dystrophic neurite") View Subject | View Object

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a(HBP:"dystrophic neurite") association a(GO:autophagosome) View Subject | View Object

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a(HBP:"dystrophic neurite") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"dystrophic neurite") View Subject | View Object

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Evidence fa08231271
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The profuse and selective accumulation of AVs in neurons in AD reflects a defect in the clearance of AVs by lysosomes rather than an abnormally elevated induction of autophagy

a(GO:autophagosome) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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MeSH
Neurons

act(a(GO:lysosome)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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MeSH
Neurons

path(MESH:"Alzheimer Disease") negativeCorrelation act(a(GO:lysosome)) View Subject | View Object

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MeSH
Neurons

path(MESH:"Alzheimer Disease") positiveCorrelation a(GO:autophagosome) View Subject | View Object

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MeSH
Neurons

Evidence a129320a82
JSON

AVs and lysosomes constitute more than 95% of the organelles in dystrophic neuritic swellings in AD and AD mouse models, implying a cargo-specific defect in axonal transport, rather than a global one.

a(GO:autophagosome) increases a(GO:organelle) View Subject | View Object

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MeSH
Alzheimer Disease

a(GO:lysosome) increases a(GO:organelle) View Subject | View Object

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MeSH
Alzheimer Disease

bp(GO:"axonal transport") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:"axonal transport") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 2a92711bc9
JSON

AVs are also enriched in APP substrates and secretases and, during autophagy, Ab peptide is generated from APP (Yu et al. 2005), although it is subsequently degraded in lysosomes under normal circumstances (Heinrich et al. 1999; Bahr et al. 2002; Florez-McClure et al. 2007).

a(GO:autophagosome) association p(HGNC:APP) View Subject | View Object

Appears in Networks:

bp(GO:"lysosomal protein catabolic process") increases deg(a(MESH:"Amyloid beta-Peptides")) View Subject | View Object

Appears in Networks:

bp(GO:autophagy) increases rxn(reactants(p(HGNC:APP)), products(a(MESH:"Amyloid beta-Peptides"))) View Subject | View Object

Appears in Networks:

p(HGNC:APP) association a(GO:autophagosome) View Subject | View Object

Appears in Networks:

Evidence ac0cf6a531
JSON

During the initiation of endocytosis, the invagination of plasmamembranes into vesicles is mediated most often by the clathrin/adaptor protein complex, but also via caveolae or bulk macropinocytosis (Lim et al. 2011).

a(GO:caveola) increases bp(GO:"plasma membrane invagination") View Subject | View Object

Appears in Networks:

bp(GO:"bulk synaptic vesicle endocytosis") increases bp(GO:"plasma membrane invagination") View Subject | View Object

Appears in Networks:

complex(GO:"clathrin complex") increases bp(GO:"plasma membrane invagination") View Subject | View Object

Appears in Networks:

Evidence 585cc4a569
JSON

Beyond influencing Ab generation and toxicity, defective endosome functioning plays a crucial Ab-independent role in the failure of retrograde NGF signaling that leads to basal forebrain cholinergic neuron degeneration in the Ts65Dn mouse model of DS (Cooper et al. 2001; Delcroix et al. 2004).

act(a(GO:endosome)) increases bp(GO:"nerve growth factor signaling pathway") View Subject | View Object

Appears in Networks:

act(a(GO:endosome)) decreases path(HBP:Neurodegeneration) View Subject | View Object

Appears in Networks:

Evidence ab6662ea41
JSON

It has recently become appreciated that ubiquitination of proteins by covalent modification tags them for elimination not only through the proteasome (the ubiquitin–proteasome system or UPS) but also through the lysosomal system.

a(GO:lysosome) increases deg(p(MESH:Proteins, pmod(Ub))) View Subject | View Object

Appears in Networks:

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(MESH:Proteins, pmod(Ub))) View Subject | View Object

Appears in Networks:

Evidence cc173528cf
JSON

A continuum of pathological changes of the lysosomal network unfolds in neurons as Alzheimer disease progresses, including dysregulation of endocytosis, increased lysosome biogenesis and, later, progressive failure of lysosomal clearance mechanisms (Fig. 6; Nixon et al. 2006).

a(GO:lysosome) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

bp(GO:"lysosomal protein catabolic process") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

bp(GO:endocytosis) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:endocytosis) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation a(GO:lysosome) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:"lysosomal protein catabolic process") View Subject | View Object

Appears in Networks:

Evidence 1cd9ca2cf2
JSON

The earliest symptoms of AD are believed to be due to synaptic dysfunction, and in this context, numerous studies have established a significant role of the UPS in the regulation of synaptic plasticity.

act(a(GO:synapse)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") association bp(GO:"regulation of synaptic plasticity") View Subject | View Object

Appears in Networks:

bp(GO:"regulation of synaptic plasticity") association bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation act(a(GO:synapse)) View Subject | View Object

Appears in Networks:

Evidence 1852e34c7a
JSON

Synaptic loss has long been documented in AD brain (Gonatas et al. 1967) and, as expected, is strongly correlated with the degree of cognitive impairment (Terry et al. 1991).

act(a(GO:synapse)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

act(a(GO:synapse)) positiveCorrelation bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

bp(GO:cognition) positiveCorrelation act(a(GO:synapse)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") negativeCorrelation act(a(GO:synapse)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence d53a7df009
JSON

In transgenic mouse models of AD, synaptic deficits have been detected prior to the formation of amyloid plaques (Hsia et al. 1999).

act(a(GO:synapse)) decreases path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 03854089ed
JSON

Similar therapeutic effects, including restoration of synaptic functions, are seen in APP mouse models after deleting cystatin C (Sun et al. 2008), by overexpressing cathepsin B (Mueller-Steiner et al. 2006), or by enhancing its activity (Butler et al. 2011).

act(a(GO:synapse)) positiveCorrelation p(HGNC:CTSB) View Subject | View Object

Appears in Networks:

p(HGNC:CST3) decreases act(a(GO:synapse)) View Subject | View Object

Appears in Networks:

p(HGNC:CTSB) positiveCorrelation act(a(GO:synapse)) View Subject | View Object

Appears in Networks:

Evidence a2a557c752
JSON

Neuronal endosome enlargement, which is not characteristically observed in other major neurodegenerative diseases, develops in pyramidal neurons of the neocortex at a stage when plaques and tangles are restricted only to the hippocampus (Braak stage 2) and not in brains of similarly aged individuals free of AD-like hippocampal pathology (Cataldo et al. 1997, 2000).

a(HBP:"Braak_Stage II") association bp(GO:"regulation of endosome size") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Neurons
MeSH
Pyramidal Cells

bp(GO:"regulation of endosome size") association path(MESH:"Neurodegenerative Diseases") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Neurons
MeSH
Pyramidal Cells

bp(GO:"regulation of endosome size") association a(HBP:"Braak_Stage II") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Neurons
MeSH
Pyramidal Cells

path(MESH:"Neurodegenerative Diseases") association bp(GO:"regulation of endosome size") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Neurons
MeSH
Pyramidal Cells

Evidence 2d7155aaaa
JSON

This finding suggests that neuropil threads may extend at both ends: Tau may aggregate and deposit first, followed by its ubiquitination.

a(HBP:"Tau aggregates") increases p(HBP:"Tau aggregates", pmod(Ub)) View Subject | View Object

Appears in Networks:

Evidence d4a0927934
JSON

In vitro experiments further showed that aggregated (recombinant) tau—but not nonaggregated (monomeric) tau—can inhibit the proteasome activity.

a(HBP:"Tau aggregates") decreases act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

Evidence 69bdb29520
JSON

This protein reactive with the initial anti-PHF sera was soon identified as tau, a microtubule-associated protein (MAP), based on its molecular weight, isoform change during development, microtubule- binding activity, and heat stability (Kosik et al. 1986; Nukina and Ihara 1986; see also Brion et al. 1985; Grundke-Iqbal et al. 1986; Wood et al. 1986; discovery of tau in PHF is reviewed in Mandelkow and Mandelkow 2011).

a(HBP:"paired helical filaments") association p(HGNC:MAPT) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT) association a(HBP:"paired helical filaments") View Subject | View Object

Appears in Networks:

Evidence 21d5b6addc
JSON

Using well-characterized antibodies to various MAPs as well as PHF polyclonal antibodies, tau had recently been established as a major component of PHFs (see above and Mandelkow and Mandelkow 2011).

a(HBP:"paired helical filaments") association p(HGNC:MAPT) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT) association a(HBP:"paired helical filaments") View Subject | View Object

Appears in Networks:

Evidence 1823ecc100
JSON

Besides the characteristic “PHF smear,” they also labeled a very small protein of ~8 kDa. Hiroshi Mori named these monoclonal antibodies DF (Dementia Filament) 1 and 2, of which the latter (DF2) was used for subsequent characterization (Mori et al. 1987).

a(HBP:"paired helical filaments") association a(MESH:Ubiquitin) View Subject | View Object

Appears in Networks:

a(MESH:Ubiquitin) association a(HBP:"paired helical filaments") View Subject | View Object

Appears in Networks:

Evidence 270708116a
JSON

By protein sequencing and MS, we identified four Ub-conjugated sites on tau (Fig. 3) and further identified K48-linked Ub chains (Morishima-Kawashima et al. 1993).

a(HBP:"paired helical filaments") association p(HBP:"Tau isoform F (441 aa)", pmod(Ub, Lys, 254)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(HBP:"paired helical filaments") association p(HBP:"Tau isoform F (441 aa)", pmod(Ub, Lys, 257)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(HBP:"paired helical filaments") association p(HBP:"Tau isoform F (441 aa)", pmod(Ub, Lys, 311)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(HBP:"paired helical filaments") association p(HBP:"Tau isoform F (441 aa)", pmod(Ub, Lys, 317)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(HBP:"paired helical filaments") association p(HBP:"Tau isoform F (441 aa)", pmod(UbK48)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HBP:"Tau isoform F (441 aa)", pmod(Ub, Lys, 254)) association a(HBP:"paired helical filaments") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HBP:"Tau isoform F (441 aa)", pmod(Ub, Lys, 257)) association a(HBP:"paired helical filaments") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HBP:"Tau isoform F (441 aa)", pmod(Ub, Lys, 311)) association a(HBP:"paired helical filaments") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HBP:"Tau isoform F (441 aa)", pmod(Ub, Lys, 317)) association a(HBP:"paired helical filaments") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HBP:"Tau isoform F (441 aa)", pmod(UbK48)) association a(HBP:"paired helical filaments") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 1ca57df2cc
JSON

However, recent work by Cripps et al. (2006) successfully used MC1 (a monoclonal specific for an abnormal PHF-like conformation of tau) to affinity purify soluble full-length tau from PHF-rich extracts of AD cortex and subject it to liquid chromatography–tandem MS (LC–MS/MS) analysis. The presence of K6, K11, and K48- linked polyubiquitinations—in addition to monoubiquitination—was observed.

a(HBP:"paired helical filaments") association p(HBP:"Tau isoform F (441 aa)", pmod(UbK48)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(HBP:"paired helical filaments") association p(HBP:"Tau isoform F (441 aa)", pmod(UbPoly, Lys, 6)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(HBP:"paired helical filaments") association p(HBP:"Tau isoform F (441 aa)", pmod(UbPoly, Lys, 11)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HBP:"Tau isoform F (441 aa)", pmod(UbK48)) association a(HBP:"paired helical filaments") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HBP:"Tau isoform F (441 aa)", pmod(UbPoly, Lys, 11)) association a(HBP:"paired helical filaments") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HBP:"Tau isoform F (441 aa)", pmod(UbPoly, Lys, 6)) association a(HBP:"paired helical filaments") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence d388360357
JSON

PHF have been associated with inhibition of the activity of the proteasome in a brain region–specific manner (Keller et al. 2000).

a(HBP:"paired helical filaments") negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

act(complex(GO:"proteasome complex")) negativeCorrelation a(HBP:"paired helical filaments") View Subject | View Object

Appears in Networks:

Evidence 5dca7e4687
JSON

Among the various molecular species of Abeta present in the brain, soluble oligomeric forms of Abeta are arguably the most plausible candidates to impair synaptic function (reviewed in Walsh and Selkoe 2004).

a(HBP:AβOs) decreases act(a(GO:synapse)) View Subject | View Object

Appears in Networks:

Evidence 9b8e41f357
JSON

Soluble Ab oligomers inhibit hippocampal long-term potentiation and alter memory and learning performance

a(HBP:AβOs) decreases bp(GO:"long-term synaptic potentiation") View Subject | View Object

Appears in Networks:

a(HBP:AβOs) decreases bp(GO:learning) View Subject | View Object

Appears in Networks:

a(HBP:AβOs) decreases bp(GO:memory) View Subject | View Object

Appears in Networks:

Evidence 82d3e41083
JSON

They also facilitate long-term depression by, among other effects, disrupting synaptic glutamate uptake (Li et al. 2009).

a(HBP:AβOs) increases bp(GO:"long-term synaptic depression") View Subject | View Object

Appears in Networks:

a(HBP:AβOs) decreases bp(GO:"L-glutamate import") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synapses

Evidence 976448edaf
JSON

Recently, it has been shown that soluble Ab oligomers isolated from AD cortex can induce tau hyperphosphorylation at AD-relevant epitopes and subsequent neuritic degeneration (Jin et al. 2011).

a(HBP:AβOs) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(HBP:AβOs) increases deg(a(MESH:Neurites)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence eb27921c00
JSON

Moreover, soluble Ab oligomers themselves can inhibit proteasomal activity (Tseng et al. 2008).

a(HBP:AβOs) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

Evidence 2a435556bd
JSON

Although less well studied as “Ab degrading proteases” than the zinc metallopeptidase family (Guenette 2003; Eckman et al. 2005), cathepsins are considered an important route for Ab/amyloid clearance (Mueller-Steiner et al. 2006; Nixon 2007; Butler et al. 2011) and human neurons may be particularly dependent on this mechanism (LeBlanc et al. 1999; reviewed in Saido and Leissring 2011).

a(MESH:Cathepsins) regulates deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:

Evidence 5cd26fae22
JSON

Cataclysmic disruption of lysosomal membranes releases hydrolases that act as both the trigger and executioner in rapid necrosis (Syntichaki et al. 2003; Kroemer et al. 2005), whereas slow release of cathepsins more likely operates through signaling pathways to trigger apoptosis (Kroemer et al. 2005).

sec(a(MESH:Cathepsins)) increases bp(GO:"apoptotic process") View Subject | View Object

Appears in Networks:

sec(a(MESH:Hydrolases)) increases path(MESH:Necrosis) View Subject | View Object

Appears in Networks:

Evidence 1c0525d948
JSON

Similar neuritic dystrophy eventually develops in all forms of AD and in mouse AD models where only FAD-causingmutant APP is overexpressed.

act(a(MESH:Neurites)) negativeCorrelation p(HGNC:APP, var("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:APP, var("?")) negativeCorrelation act(a(MESH:Neurites)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence fcaccb4275
JSON

In addition, DF2 intensely labeled the classical granulovacuolar changes in the hippocampus in AD and other neurodegenerative disorders (Fig. 1, inset).

a(MESH:Ubiquitin) association path(HBP:"granulovacuolar degeneration") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Alzheimer Disease
MeSH
Neurodegenerative Diseases

path(HBP:"granulovacuolar degeneration") association a(MESH:Ubiquitin) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Alzheimer Disease
MeSH
Neurodegenerative Diseases

Evidence 5cfe823abe
JSON

Second, there is conjugation of the ATP-activated Ub to an E2 protein (i.e., a Ub-conjugating enzyme).

act(a(MESH:Ubiquitin)) increases complex(a(MESH:Ubiquitin), p(HGNC:UBA2)) View Subject | View Object

Appears in Networks:

Evidence cf9b410365
JSON

Ubiquitin, the crucial signal for efficient sorting of proteins into the MVB (Babst et al. 1997), initiates this process, which is mediated by a group of ESCRT complexes (endosomal sorting complex required for transport; Hurley 2010).

a(MESH:Ubiquitin) increases tloc(a(MESH:Proteins), fromLoc(GO:cytoplasm), toLoc(GO:"multivesicular body")) View Subject | View Object

Appears in Networks:

complex(GO:"ESCRT complex") regulates tloc(a(MESH:Proteins), fromLoc(GO:cytoplasm), toLoc(GO:"multivesicular body")) View Subject | View Object

Appears in Networks:

Evidence d4b2a87946
JSON

In CMA, cytosolic proteins containing a KFERQ motif (including proteins pathogenic in some neurodegenerative diseases) are selectively targeted by certain chaperones to the lysosomal lumen for degradation (Arias et al. 2011).

bp(GO:"chaperone-mediated autophagy") increases tloc(a(MESH:Proteins), fromLoc(GO:cytosol), toLoc(GO:"lysosomal lumen")) View Subject | View Object

Appears in Networks:

Evidence 8f761efe46
JSON

Incomplete charperone-mediated autophagy of tau generates fragments that aggregate and are cleared by macroautophagy (Wang et al. 2009).

bp(GO:"chaperone-mediated autophagy") increases deg(p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

bp(GO:macroautophagy) increases deg(p(HGNC:MAPT, frag("?"))) View Subject | View Object

Appears in Networks:

deg(p(HGNC:MAPT)) increases p(HGNC:MAPT, frag("?")) View Subject | View Object

Appears in Networks:

Evidence 32c84dd5e6
JSON

However, Ub was found to have other functional roles; for example, a proportion of histone (H)2B is ubiquitinated in a way that has a role in the transcription.

bp(GO:"histone H2B ubiquitination") association bp(MESH:"Transcription, Genetic") View Subject | View Object

Appears in Networks:

bp(MESH:"Transcription, Genetic") association bp(GO:"histone H2B ubiquitination") View Subject | View Object

Appears in Networks:

Evidence d62be44ad7
JSON

Pathological Rab5 activation driving endocytic dysfunction in AD may negatively impact longterm potentiation (LTP) and long-term depression (LTD) aspects of synaptic plasticity closely associated with learning and memory (Kessels et al. 2009)

bp(GO:"long-term synaptic depression") negativeCorrelation act(p(HGNC:RAB5A)) View Subject | View Object

Appears in Networks:

bp(GO:"long-term synaptic potentiation") negativeCorrelation act(p(HGNC:RAB5A)) View Subject | View Object

Appears in Networks:

bp(GO:endocytosis) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

act(p(HGNC:RAB5A)) decreases bp(GO:endocytosis) View Subject | View Object

Appears in Networks:

act(p(HGNC:RAB5A)) negativeCorrelation bp(GO:"long-term synaptic potentiation") View Subject | View Object

Appears in Networks:

act(p(HGNC:RAB5A)) negativeCorrelation bp(GO:"long-term synaptic depression") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:endocytosis) View Subject | View Object

Appears in Networks:

Evidence 67f0c932c5
JSON

Microautophagy involves the nonselective entry of small quantities of cytoplasm into lysosomes or late endosomes/MVBs when the limiting membranes of these compartments invaginate and pinch off small vesicles for digestion within the lumen (Sahu et al. 2011).

bp(GO:"lysosomal microautophagy") increases tloc(a(GO:cytoplasm), fromLoc(GO:intracellular), toLoc(GO:lysosome)) View Subject | View Object

Appears in Networks:

bp(GO:"lysosomal microautophagy") increases tloc(a(GO:cytoplasm), fromLoc(GO:intracellular), toLoc(GO:"multivesicular body")) View Subject | View Object

Appears in Networks:

Evidence c357d5d857
JSON

Similar autophagy pathology is observed when lysosomal proteolysis is inhibited (Ivy et al. 1984; Koike et al. 2005; Yang et al. 2008).

bp(GO:"lysosomal protein catabolic process") positiveCorrelation bp(GO:autophagy) View Subject | View Object

Appears in Networks:

bp(GO:autophagy) positiveCorrelation bp(GO:"lysosomal protein catabolic process") View Subject | View Object

Appears in Networks:

Evidence 63583fdc17
JSON

Indeed, when lysosomal proteolysis is inhibited by blocking acidification or directly inhibiting cathepsins,axonal transport of autophagy-related compartments is selectively slowed and intermittently interrupted.

bp(GO:"lysosomal protein catabolic process") increases bp(GO:"axonal transport") View Subject | View Object

Appears in Networks:

Evidence 6ba3b0ee9d
JSON

A close connection between lysosomal network dysfunction and mechanisms of neurodegeneration is well documented (McCray et al. 2008; Nixon et al. 2008; Bellettato et al. 2010; Cherra et al. 2010).

bp(GO:"lysosomal protein catabolic process") decreases path(HBP:Neurodegeneration) View Subject | View Object

Appears in Networks:

Evidence 6542ec1fa0
JSON

In APP transgenic mouse models of AD, undigested autophagy substrates including LC3-II, p62, and ubiquitinated proteins accumulate in neuronal AVs, establishing that autophagic protein turnover in lysosomes is impeded (Yang et al. 2011).

bp(GO:"lysosomal protein catabolic process") decreases p(HGNC:MAP1LC3B) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

bp(GO:"lysosomal protein catabolic process") decreases p(HGNC:SQSTM1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

bp(GO:"lysosomal protein catabolic process") decreases p(MESH:Proteins, pmod(Ub)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence eb5c912fa7
JSON

Stimulating lysosomal proteolytic efficiency in the TgCRND8 APP mouse model by deleting an endogenous inhibitor of lysosomal cysteine proteases (cystatin B) rescues lysosomal pathology, eliminates abnormal autolysosomal accumulation of autophagy substrates, including Ab, decreases Ab and amyloid deposition, and ameliorates learning and memory deficits (Yang et al. 2011)

bp(GO:"lysosomal protein catabolic process") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

bp(GO:"lysosomal protein catabolic process") increases bp(GO:learning) View Subject | View Object

Appears in Networks:

bp(GO:"lysosomal protein catabolic process") increases bp(GO:memory) View Subject | View Object

Appears in Networks:

Evidence 16af426ba4
JSON

Interactions between FAD-mutant forms of APP and APP binding protein (APP-BP1) on endosomes also initiate pathological rab5 activation, which was shown to promote a neuronal apoptosis cascade (Laifenfeld et al. 2007).

bp(GO:"neuron death") positiveCorrelation act(p(HGNC:RAB5A)) View Subject | View Object

Appears in Networks:

complex(a(GO:endosome), p(HGNC:APP, var("?")), p(HGNC:NAE1)) increases act(p(HGNC:RAB5A)) View Subject | View Object

Appears in Networks:

act(p(HGNC:RAB5A)) positiveCorrelation bp(GO:"neuron death") View Subject | View Object

Appears in Networks:

Evidence 1b5e647519
JSON

Interdependence of the proteasome and lysosomal system is also suggested by observations that, when proteasome activity is inhibited, proteins accumulate that become substrates for autophagy (Fortun et al. 2003)

bp(GO:"proteasomal protein catabolic process") negativeCorrelation bp(GO:autophagy) View Subject | View Object

Appears in Networks:

bp(GO:"proteasomal protein catabolic process") decreases a(MESH:Proteins) View Subject | View Object

Appears in Networks:

bp(GO:autophagy) negativeCorrelation bp(GO:"proteasomal protein catabolic process") View Subject | View Object

Appears in Networks:

Evidence 0bd4a57387
JSON

For example, p62, an adaptor protein for autophagy, also influences proteasomal degradation, whereas VCP/p97 acting through p62 and ubiquitin regulates both the proteasome-dependent endoplasmic reticulum–associated degradation (ERAD) pathway and aspects of autophagosome maturation (Tresse et al. 2010).

bp(GO:"proteasomal protein catabolic process") association p(HGNC:SQSTM1) View Subject | View Object

Appears in Networks:

composite(a(MESH:Ubiquitin), p(HGNC:SQSTM1)) increases act(p(HGNC:VCP)) View Subject | View Object

Appears in Networks:

p(HGNC:SQSTM1) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

p(HGNC:SQSTM1) association bp(GO:"proteasomal protein catabolic process") View Subject | View Object

Appears in Networks:

act(p(HGNC:VCP)) regulates bp(GO:"ERAD pathway") View Subject | View Object

Appears in Networks:

act(p(HGNC:VCP)) regulates a(GO:autophagosome) View Subject | View Object

Appears in Networks:

Evidence a8cc353415
JSON

The UPS is also critically involved in learning and memory.

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") association bp(GO:learning) View Subject | View Object

Appears in Networks:

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") association bp(GO:memory) View Subject | View Object

Appears in Networks:

bp(GO:learning) association bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

bp(GO:memory) association bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

Evidence d6cd663aad
JSON

This and numerous related findings suggest that degradation of certain critical proteins by the UPS is required during long-term memory formation. One of these proteins is arc, a negative regulator of synaptic strength that promotes the internalization of AMPA receptors and is degraded via the E3 ligase, UBE3A (Greer et al. 2010).

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:ARC)) View Subject | View Object

Appears in Networks:

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases bp(GO:"long-term memory") View Subject | View Object

Appears in Networks:

p(HGNC:ARC) regulates bp(GO:"synapse maturation") View Subject | View Object

Appears in Networks:

p(HGNC:UBE3A) increases deg(p(HGNC:ARC)) View Subject | View Object

Appears in Networks:

Evidence 3df3d413ed
JSON

Similar endosomal anomalies develop gradually in Down syndrome brain, beginning decades before the appearance of classical AD pathology (Cataldo et al. 2000).

bp(GO:"regulation of endosome size") negativeCorrelation path(MESH:"Down Syndrome") View Subject | View Object

Appears in Networks:

path(MESH:"Down Syndrome") negativeCorrelation bp(GO:"regulation of endosome size") View Subject | View Object

Appears in Networks:

Evidence 1fa17dc63e
JSON

Genes related to endocytosis, such as Rab5,Rab7, and Rab4, are among the earliest groups to showup-regulated transcription in AD(Ginsberg et al. 2010), and their corresponding proteins are abnormally recruited to endosomes, where they promote fusion and abnormal enlargement of early and late endosomes (Cataldo et al. 1997, 2008).

bp(GO:"regulation of endosome size") association p(HGNC:RAB7A) View Subject | View Object

Appears in Networks:

bp(GO:"regulation of endosome size") association p(HGNC:RAB5A) View Subject | View Object

Appears in Networks:

bp(GO:"regulation of endosome size") association p(HGNC:RAB4A) View Subject | View Object

Appears in Networks:

p(HGNC:RAB4A) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:RAB4A) increases complex(a(GO:"early endosome"), a(GO:"late endosome")) View Subject | View Object

Appears in Networks:

p(HGNC:RAB4A) association bp(GO:"regulation of endosome size") View Subject | View Object

Appears in Networks:

p(HGNC:RAB5A) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:RAB5A) increases complex(a(GO:"early endosome"), a(GO:"late endosome")) View Subject | View Object

Appears in Networks:

p(HGNC:RAB5A) association bp(GO:"regulation of endosome size") View Subject | View Object

Appears in Networks:

p(HGNC:RAB7A) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:RAB7A) increases complex(a(GO:"early endosome"), a(GO:"late endosome")) View Subject | View Object

Appears in Networks:

p(HGNC:RAB7A) association bp(GO:"regulation of endosome size") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:RAB7A) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:RAB5A) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:RAB4A) View Subject | View Object

Appears in Networks:

Evidence 7e4bd30d68
JSON

Although key to the survival of all cells, endocytosis supports unique neuronal functions, including aspects of synaptic transmission and plasticity underlying memory and learning.

bp(GO:"regulation of synaptic plasticity") association bp(GO:endocytosis) View Subject | View Object

Appears in Networks:

bp(GO:endocytosis) increases bp(GO:learning) View Subject | View Object

Appears in Networks:

bp(GO:endocytosis) increases act(a(MESH:Neurons)) View Subject | View Object

Appears in Networks:

bp(GO:endocytosis) association bp(GO:"regulation of synaptic plasticity") View Subject | View Object

Appears in Networks:

bp(GO:endocytosis) increases bp(GO:memory) View Subject | View Object

Appears in Networks:

bp(GO:endocytosis) increases bp(MESH:"Synaptic Transmission") View Subject | View Object

Appears in Networks:

Evidence 5a88068c6a
JSON

Autophagy may also modulate synaptic plasticity, which involves structural remodeling of nerve terminals (Boland et al. 2006) and the trafficking and degradation of receptors and other synaptic proteins (Leil et al. 2004; Rowland et al. 2006).

bp(GO:"regulation of synaptic plasticity") association bp(GO:autophagy) View Subject | View Object

Appears in Networks:

bp(GO:autophagy) association bp(GO:"regulation of synaptic plasticity") View Subject | View Object

Appears in Networks:

Evidence 5987033ee7
JSON

The acidic environment in lysosomes is particularly favorable for the initial stages of Ab oligomerization (Peralvarez-Marin et al. 2008).

bp(GO:"response to acidic pH") increases a(HBP:"amyloid-beta oligomers") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Lysosomes

Evidence e5179e81ce
JSON

AD is the most common of numerous age-associated brain diseases, and the activity of brain proteasomes appears to decline with age (Keller et al. 2002).

bp(GO:aging) negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

act(complex(GO:"proteasome complex")) negativeCorrelation bp(GO:aging) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 55a5789feb
JSON

Beyond an age-related reduction (Keller et al. 2002), proteasome activities decrease in AD in a brain region–specific manner, particularly in hippocampus, parahippocampal gyrus, superior and middle temporal gyri, and the inferior parietal lobule (Keller et al. 2000), areas that are especially critical for long-term memory formation.

bp(GO:aging) negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parahippocampal Gyrus
MeSH
Parietal Lobe
MeSH
Temporal Lobe
MeSH
Alzheimer Disease

act(complex(GO:"proteasome complex")) negativeCorrelation bp(GO:aging) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Parahippocampal Gyrus
MeSH
Parietal Lobe
MeSH
Temporal Lobe
MeSH
Alzheimer Disease

Evidence 249bffc88b
JSON

The lysosomal system, and specifically the autophagic pathway, is the principal mechanism for degrading proteins with long half-lives and is the only system in cells for degrading organelles and large protein aggregates or inclusions.

bp(GO:autophagy) increases deg(a(GO:organelle)) View Subject | View Object

Appears in Networks:

bp(GO:autophagy) increases deg(a(HBP:"protein aggregates")) View Subject | View Object

Appears in Networks:

Evidence 5b3d101d04
JSON

Recently, protein aggregates and certain organelles have been shown to be tagged with ubiquination for selective removal by autophagy (Narendra et al. 2009; Dikic et al. 2010; Youle et al. 2011), a degradative process previously believed to be only nonselective

bp(GO:autophagy) increases deg(a(GO:organelle)) View Subject | View Object

Appears in Networks:

bp(GO:autophagy) increases deg(a(HBP:"protein aggregates")) View Subject | View Object

Appears in Networks:

Evidence dac1e0c75d
JSON

Autophagy is the cell’s principal degradative pathway for eliminating unwanted organelles and long-lived proteins and for clearing damaged, aggregated, or obsolete proteins (Wong et al. 2010).

bp(GO:autophagy) increases deg(a(GO:organelle)) View Subject | View Object

Appears in Networks:

bp(GO:autophagy) increases deg(a(HBP:"protein aggregates")) View Subject | View Object

Appears in Networks:

Evidence d0500a859b
JSON

Inhibiting autophagy by genetically deleting components of the sequestration machinery causes ubiquitinated protein aggregates to appear in neurons, reflecting additional negative effects on the UPS (Korolchuket al. 2009a,b).

bp(GO:autophagy) increases deg(p(HBP:"protein aggregates", pmod(Ub))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

Evidence 50936f6294
JSON

Indeed, many recent studies suggest the involvement of autophagy in the pathogenesis of AD

bp(GO:autophagy) association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") association bp(GO:autophagy) View Subject | View Object

Appears in Networks:

Evidence 7ff6173f27
JSON

A second route to lysosomes, the endocytic pathway, delivers extracellular material and plasma membrane constituents to lysosomes under the direction of specific targeting signals (Nixon 2004).

bp(GO:endocytosis) increases tloc(a(GO:"intrinsic component of plasma membrane"), fromLoc(GO:"plasma membrane"), toLoc(GO:lysosome)) View Subject | View Object

Appears in Networks:

Evidence 78a39ed185
JSON

During macroautophagy, an elongated “isolation” membrane created from a preautophagosomal structure sequesters a region of cytoplasm to form a double- membrane-limited autophagosome (Fig. 5).

bp(GO:macroautophagy) increases a(GO:autophagosome) View Subject | View Object

Appears in Networks:

Evidence 35d48f28ab
JSON

The proteasome selectively degrades normal proteins (mainly those with short half-lives) and abnormal proteins, which are earmarked for elimination by a process involving their conjugation to ubiquitin (Ub; Goldberg 2003).

complex(GO:"proteasome complex") increases deg(p(MESH:Proteins, pmod(Ub))) View Subject | View Object

Appears in Networks:

Evidence 9b55cb20ca
JSON

Proteins tagged with chains of four or more K48-linked multiubiquitins provide the strongest signal for degradation by the 26S proteasome, because a chain of at least four Ub moieties is required for substrate recognition by the 26S proteasome complex.

complex(GO:"proteasome complex") increases deg(p(MESH:Proteins, pmod(UbK48))) View Subject | View Object

Appears in Networks:

Evidence f4fb8c3ffc
JSON

Another study of AD brain tissues showed that hyperphosphorylated tau was bound to the proteasome, presumably to the 19S cap portion, and the more tau that was bound, the more that proteasomes appeared to be inhibited (Keck et al. 2003).

act(complex(GO:"proteasome complex")) negativeCorrelation complex(a(GO:"proteasome regulatory particle"), p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

complex(a(GO:"proteasome regulatory particle"), p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 0e402a09f7
JSON

During the induction of long-term facilitation in the snail, the regulatory subunit of cAMP-dependent protein kinase (PKA) is ubiquitinated and degraded by the proteasome, generating persistently activated PKA (Hegde et al. 1993).

complex(GO:"proteasome complex") increases deg(p(FPLX:PKA, pmod(Ub))) View Subject | View Object

Appears in Networks:

deg(p(FPLX:PKA, pmod(Ub))) increases act(p(FPLX:PKA)) View Subject | View Object

Appears in Networks:

Evidence 47110660ec
JSON

As regards the proteasome, both the ATP-dependent 26S proteasome and the ATP-independent 20S proteasome have been reported to degrade normal, soluble tau (Cardozo et al. 2002; Zhang et al. 2005).

complex(GO:"proteasome complex") increases deg(p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

p(HBP:"20 S Proteasome") increases deg(p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

Evidence 7a49a2c4a9
JSON

In 1997, a-synuclein was shown to be the principal component of Lewy bodies (Spillantini et al. 1997). The accumulated a-synuclein was then shown to be ubiquitinated (Hasegawa et al. 2002).

p(HGNC:SNCA) positiveCorrelation p(HGNC:SNCA, pmod(Ub)) View Subject | View Object

Appears in Networks:

p(HGNC:SNCA) increases complex(a(GO:"Lewy body"), p(HGNC:SNCA)) View Subject | View Object

Appears in Networks:

p(HGNC:SNCA, pmod(Ub)) positiveCorrelation p(HGNC:SNCA) View Subject | View Object

Appears in Networks:

Evidence d493e85632
JSON

Amphisomes formed by the fusion of autophagosomes with early endosomes or MVBs/late endosomes are especially important in neurons, where a considerable proportion of endocytosed cargo is directed to the autophagic pathway prior to being degraded by lysosomes (Larsen et al. 2002).

complex(a(GO:"early endosome"), a(GO:autophagosome)) increases a(GO:amphisome) View Subject | View Object

Appears in Networks:

Evidence 8f087181b1
JSON

Sequestered material within autophagosomes is digested when lysosomes or late endosomes fuse with the outer membrane of the autophagosome (Gordon et al. 1988).

complex(a(GO:"late endosome"), a(GO:autophagosome), a(GO:lysosome)) increases deg(a(MESH:Proteins)) View Subject | View Object

Appears in Networks:

Evidence c2ffbf72a1
JSON

Next, ubiquilin-1 has been reported to be genetically linked to AD

p(HGNC:UBQLN1) association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:UBQLN1) View Subject | View Object

Appears in Networks:

Evidence 9eb7392efd
JSON

Ubiquilin-1 interacts with both proteasomes and ubiquitinated proteins and regulates the proteasomal degradation of various proteins, including presenilin 1 (Haapasalo et al. 2010).

p(HGNC:UBQLN1) increases complex(a(GO:"proteasome complex"), p(HGNC:UBQLN1)) View Subject | View Object

Appears in Networks:

p(HGNC:UBQLN1) increases complex(p(HGNC:UBQLN1), p(MESH:Proteins, pmod(Ub))) View Subject | View Object

Appears in Networks:

p(HGNC:UBQLN1) regulates deg(p(HGNC:PSEN1)) View Subject | View Object

Appears in Networks:

Evidence f7b2e62ab2
JSON

Based on these various findings, it has been speculated that small aggregates of PHFs may bind to the cap portion of the 26S proteasome and inhibit its activity

complex(a(GO:"proteasome regulatory particle"), a(HBP:"paired helical filaments")) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

Appears in Networks:

Evidence ead3b86216
JSON

Ubiquitinated target proteins bind to the 19S cap (RP), which has a Ub binding site and ATPase activity, and this leads to cleavage of Ub moieties from the target by deubiquitinating enzymes, unfolds the polypeptides and sends them to the narrow channel of the 20S core particle.

complex(a(GO:"proteasome regulatory particle"), p(MESH:Proteins, pmod(Ub))) increases tloc(a(MESH:Proteins), fromLoc(GO:"proteasome regulatory particle"), toLoc(HBP:"20 S Proteasome")) View Subject | View Object

Appears in Networks:

p(MESH:Proteins, pmod(Ub)) increases complex(a(GO:"proteasome regulatory particle"), p(MESH:Proteins, pmod(Ub))) View Subject | View Object

Appears in Networks:

Evidence dffd6ee4e6
JSON

Third, there is ligation of Ub with an epsilon-amino group of lysine in the target protein by an E3 ligase. E3 ligase binds both the target protein and the E2–Ub complex; thousands of substrate- specific E3s ensure selective protein tagging and degradation.

p(MESH:Proteins, pmod(Ub)) increases deg(p(MESH:Proteins, pmod(Ub))) View Subject | View Object

Appears in Networks:

complex(a(MESH:Proteins), a(MESH:Ubiquitin), p(HGNC:UBA2), p(HGNC:UBA3)) increases p(MESH:Proteins, pmod(Ub)) View Subject | View Object

Appears in Networks:

p(HGNC:UBA3) increases complex(a(MESH:Proteins), a(MESH:Ubiquitin), p(HGNC:UBA2), p(HGNC:UBA3)) View Subject | View Object

Appears in Networks:

Evidence 9f85c3b4c8
JSON

App promoter polymorphisms that increase APP expression are also associated with early-onset AD (Athan et al. 2002).

p(HGNC:APP, var("?")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:APP, var("?")) View Subject | View Object

Appears in Networks:

Evidence 836df09d7f
JSON

These findings support a longstanding hypothesis that the App gene on the trisomic copy of human chromosome 21 (HSA21) in Down syndrome (DS) is principally responsible for the invariant early development of AD in DS individuals (Margallo-Lana et al. 2004).

p(HGNC:APP, var("?")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Down Syndrome

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:APP, var("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Down Syndrome

Evidence ac86cc5d14
JSON

In DS, the extra copy of App causes endocytic up-regulation and endosome pathology similar to that seen at the earliest stages of sporadic AD, but beginning even earlier

p(HGNC:APP, var("?")) increases bp(GO:endocytosis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Down Syndrome

Evidence 3136615528
JSON

As described above, it has also been found that the 20S proteasome interacts with tau aggregates (Keck et al. 2003).

p(HBP:"20 S Proteasome") increases complex(a(HBP:"Tau aggregates"), p(HBP:"20 S Proteasome")) View Subject | View Object

Appears in Networks:

Evidence aca79dbf39
JSON

On the other hand, it has been reported that the E3 ligase CHIP (carboxyl terminus of the Hsc70-interacting protein) binds to tau and is involved in the degradation of abnormal forms of tau, including insoluble tau and hyperphosphorylated tau, coordinately with Hsp70 (Petrucelli et al. 2004; Dickey et al. 2006).

complex(p(HGNC:HSPA8), p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)), p(HGNC:STUB1)) increases deg(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) View Subject | View Object

Appears in Networks:

p(HGNC:STUB1) increases complex(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)), p(HGNC:STUB1)) View Subject | View Object

Appears in Networks:

Evidence 82f7ff9185
JSON

The first step is activation of the carboxyl terminus of Ub by an E1 protein (i.e., a Ub-activating enzyme), which consumes ATP.

composite(a(CHEBI:ATP), p(HGNC:UBA1)) increases act(a(MESH:Ubiquitin)) View Subject | View Object

Appears in Networks:

Evidence 4996485d21
JSON

Acceleration of endosome pathology is also seen in individuals who inherit the 14 allele of APOE, a key mediator of neuronal cholesterol transport and the major genetic risk factor for late-onset AD (Cataldo et al. 2000).

g(HBP:"APOE e4") regulates bp(GO:"cholesterol transport") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

g(HBP:"APOE e4") association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

path(MESH:"Alzheimer Disease") association g(HBP:"APOE e4") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

Evidence f2ff76a7d8
JSON

Expression of the ApoE epsilon 4 allele, but not ApoE epsilon 3, in mice administered a neprilysin inhibitor increases Ab immunoreactivity in lysosomes and causes neurodegeneration of hippocampal CA1, entorhinal,and septal neurons (Belinson et al. 2008).

g(HBP:"APOE e4") increases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Lysosomes

g(HBP:"APOE e4") increases path(HBP:Neurodegeneration) View Subject | View Object

Appears in Networks:
Annotations
MeSH
CA1 Region, Hippocampal
MeSH
Neurons

Evidence 786c2860bf
JSON

ApoE epsilon4 that trafficks to lysosomes more readily than ApoE epsilon3, promotes leakage of acid hydrolases, and induces apoptosis in cultured neuronal cells by forming membrane-damaging intermediates in the low-pHenvironment (Ji et al. 2002).

g(HBP:"APOE e4") increases bp(GO:"apoptotic process") View Subject | View Object

Appears in Networks:

Evidence a6de739cc8
JSON

Activated PKA induces transcription of ApUCH (UCH-L1 in mammals), a deubiquitinating enzyzme, which has been found to be critical for the induction of long-term facilitation (Hegde et al. 1997).

act(p(FPLX:PKA)) increases p(HGNC:UCHL1) View Subject | View Object

Appears in Networks:

Evidence 30619e5eec
JSON

Recently, these effects of increased App dosage were shown to be mediated specifically by the b-cleaved carboxy-terminal fragment of APP, bCTF (Jiang et al. 2010), which binds to a complex of signaling molecules on endosomes that pathologically activates rab5 (S Kim and RA Nixon, unpubl.).

p(HBP:"APP C-terminally truncated carboxyl-terminal fragments") increases act(p(HGNC:RAB5A)) View Subject | View Object

Appears in Networks:

Evidence ea8e52857d
JSON

The currently prevailing view of the temporal involvement of Ub in PHF evolution is that the aggregation of hyperphosphorylated tau is followed by ubiquitination

p(HBP:"Tau aggregates", pmod(HBP:hyperphosphorylation)) increases p(HBP:"Tau aggregates", pmod(HBP:hyperphosphorylation), pmod(Ub)) View Subject | View Object

Appears in Networks:

Evidence dd839e9526
JSON

UBB+1 protein accumulates in brains affected by AD and other diseases such as Pick’s disease and Huntington’s disease (Fischer et al. 2003).

p(HBP:"UBB+1") positiveCorrelation path(MESH:"Niemann-Pick Diseases") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

p(HBP:"UBB+1") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") positiveCorrelation p(HBP:"UBB+1") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Niemann-Pick Diseases") positiveCorrelation p(HBP:"UBB+1") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence 222c4ade31
JSON

Indeed, transgenic mice expressing UBB+1 have an impaired UPS and show contextual memory deficits in both water maze and fear conditioning paradigms, without specific neuropathological findings (Fischer et al. 2009).

p(HBP:"UBB+1") decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

p(HBP:"UBB+1") decreases bp(GO:memory) View Subject | View Object

Appears in Networks:

Evidence de94419ce8
JSON

The resulting polyubiquitinated UBB+1 cannot be degraded by proteasomes and impairs the UPS (Lam et al. 2000), which may induce neurotoxicity.

p(HBP:"UBB+1", pmod(UbPoly)) decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

p(HBP:"UBB+1", pmod(UbPoly)) decreases deg(p(HBP:"UBB+1", pmod(UbPoly))) View Subject | View Object

Appears in Networks:

Evidence b9c49cd27a
JSON

In the absence of PS1, the V0a1 subunit of v-ATPase is not N-glycosylated in the ER and is degraded before sufficient amounts can be delivered to autolysosomes/lysosomes to support lysosomal acidification.

p(HGNC:ATP6V0A1, pmod(NGlyco)) increases bp(GO:"pH reduction") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Lysosomes

p(HGNC:PSEN1) increases p(HGNC:ATP6V0A1, pmod(NGlyco)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Lysosomes

Evidence df37914516
JSON

Acid hydrolases, including cathepsins, are delivered from the trans-Golgi network (TGN) to MVBs/late endosomes by either of two mannose-6- phosphate receptors: cation-dependent 46 kDa MPR (CD-MPR) and cation-independent 215 kDa MPR (CI-MPR; Mullins et al. 2001).

p(HGNC:IGF2R) increases tloc(a(MESH:Cathepsins), fromLoc(GO:"trans-Golgi network"), toLoc(GO:"multivesicular body")) View Subject | View Object

Appears in Networks:

p(HGNC:M6PR) increases tloc(a(MESH:Cathepsins), fromLoc(GO:"trans-Golgi network"), toLoc(GO:"multivesicular body")) View Subject | View Object

Appears in Networks:

Evidence cb04dae95b
JSON

In AD, tau is ubiquitinated, in Parkinson’s disease and dementia with Lewy bodies, it is a-synuclein, and in ALS and FTLD-U, it is TDP-43

p(HGNC:MAPT, pmod(Ub)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:SNCA, pmod(Ub)) positiveCorrelation path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:

p(HGNC:SNCA, pmod(Ub)) positiveCorrelation path(MESH:Dementia) View Subject | View Object

Appears in Networks:

p(HGNC:TARDBP, pmod(Ub)) positiveCorrelation path(MESH:"Amyotrophic Lateral Sclerosis") View Subject | View Object

Appears in Networks:

path(MESH:"Parkinson Disease") positiveCorrelation p(HGNC:SNCA, pmod(Ub)) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ub)) View Subject | View Object

Appears in Networks:

path(MESH:"Amyotrophic Lateral Sclerosis") positiveCorrelation p(HGNC:TARDBP, pmod(Ub)) View Subject | View Object

Appears in Networks:

path(MESH:Dementia) positiveCorrelation p(HGNC:SNCA, pmod(Ub)) View Subject | View Object

Appears in Networks:

Evidence 29de74c237
JSON

The E3 ligase Parkin, a protein implicated in Parkinson’s disease, creates an autophagy signal on mitochondria and also tags proteins elsewhere for proteasomal degradation (Yoshii et al. 2011).

p(HGNC:PRKN) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:PRKN) increases bp(GO:mitophagy) View Subject | View Object

Appears in Networks:

p(HGNC:PRKN) increases bp(GO:"proteasomal protein catabolic process") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:PRKN) View Subject | View Object

Appears in Networks:

Evidence 1786a34c2f
JSON

Beyond its role as a component of g-secretase, Presenilin 1 (PS1) is required for lysosome acidification, which is needed to activate cathepsins and other hydrolases that carry out digestion during autophagy (Lee et al. 2010).

p(HGNC:PSEN1) increases bp(GO:"pH reduction") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Lysosomes

p(HGNC:PSEN1) increases act(a(MESH:Cathepsins)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Lysosomes

Evidence b158cf2911
JSON

That presenilin 1 mutations, which are a cause of early-onset familial AD, impede lysosome proteolysis and accelerate neuritic dystrophy also supports a primary role for failure of proteolytic clearance (Lee et al. 2010).

p(HGNC:PSEN1, var("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:PSEN1, var("?")) decreases bp(GO:"lysosomal protein catabolic process") View Subject | View Object

Appears in Networks:

p(HGNC:PSEN1, var("?")) decreases act(a(HBP:Neurites)) View Subject | View Object

Appears in Networks:

Evidence ab80a1e90f
JSON

These observations suggest how PS1 mutations, which impede lysosomal acidification (Lee et al. 2010), may markedly accelerate and amplify neuritic dystrophy in AD

p(HGNC:PSEN1, var("?")) decreases bp(GO:"pH reduction") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Lysosomes
MeSH
Alzheimer Disease

p(HGNC:PSEN1, var("?")) decreases act(a(MESH:Neurites)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Lysosomes
MeSH
Alzheimer Disease

Evidence ae3f527367
JSON

Still other cargoes reach late endosomes when Rab7 and its effectors replace Rab5 and initiate further endosomal maturation (Poteryaev et al. 2010).

p(HGNC:RAB7A) increases a(GO:endosome) View Subject | View Object

Appears in Networks:

Evidence 859f38d798
JSON

Conversely, deletion of the neuronal rab5 GEF, rin1, reduces rab5 activation, increases LTP induction in the amygdala, and enhances fear learning and memory, most likely by increasing surface levels of AMPA receptors (Dhaka et al. 2003).

p(HGNC:RIN1) increases act(p(HGNC:RAB5A)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Amygdala

p(HGNC:RIN1) decreases bp(GO:"long-term synaptic potentiation") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Amygdala

p(HGNC:RIN1) decreases bp(GO:"fear response") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Amygdala

p(HGNC:RIN1) decreases bp(GO:memory) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Amygdala

p(HGNC:RIN1) decreases a(MESH:"Receptors, AMPA") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Amygdala

Evidence 39dd6f31f0
JSON

In this regard, the entity of frontotemporal lobar degeneration (FTLD) with Ub-positive/tau-negative inclusions was described later, and TDP43 was identified as the ubiquitinated protein in both this disorder and ALS (Neuman et al. 2006).

p(HGNC:TARDBP, pmod(Ub)) positiveCorrelation path(MESH:"Amyotrophic Lateral Sclerosis") View Subject | View Object

Appears in Networks:

p(HGNC:TARDBP, pmod(Ub)) positiveCorrelation path(MESH:"Frontotemporal Lobar Degeneration") View Subject | View Object

Appears in Networks:

path(MESH:"Amyotrophic Lateral Sclerosis") positiveCorrelation p(HGNC:TARDBP, pmod(Ub)) View Subject | View Object

Appears in Networks:

path(MESH:"Frontotemporal Lobar Degeneration") positiveCorrelation p(HGNC:TARDBP, pmod(Ub)) View Subject | View Object

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Evidence 5c33f76761
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An E4 enzyme catalyzes the polyubiquitination of the target substrate that is bound to the E2–E3 complexes

p(HGNC:UBE4A) increases bp(GO:"protein polyubiquitination") View Subject | View Object

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Evidence f15955d8ba
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An intronic polymorphism involving alternative splicing of exon 8 in the ubiquilin 1 gene (UBQLN1), which is genetically located near a well-established linkage peak for AD on chromosome 9q22, has been associated with increased risk for late-onset AD (Bertram et al. 2005).

p(HGNC:UBQLN1, var("?")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:UBQLN1, var("?")) View Subject | View Object

Appears in Networks:

Evidence f20eb2b34f
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Although UCH-L1 is genetically associated with Parkinson’s disease (i.e., it is the PARK5 gene; Belin and Westerlund 2008), it has also been implicated in the pathogenesis of AD

p(HGNC:UCHL1) association path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:

p(HGNC:UCHL1) association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:UCHL1) View Subject | View Object

Appears in Networks:

path(MESH:"Parkinson Disease") association p(HGNC:UCHL1) View Subject | View Object

Appears in Networks:

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.