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PubMed: 18930136

Title
Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection.
Journal
Biochimica et biophysica acta
Volume
1782
Issue
None
Pages
691-9
Date
2008-12-01
Authors
Nedelsky NB | Taylor JP | Todd PK

Evidence 1c4c0fec2d
JSON

Recent evidence suggests that the autophagic turnover of amyloid beta precursor protein (APP) may underlie the generation of toxic amyloid-β species [61].

a(CHEBI:"amyloid-beta") association deg(p(HGNC:APP)) View Subject | View Object

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

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deg(p(HGNC:APP)) association a(CHEBI:"amyloid-beta") View Subject | View Object

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Evidence 18321cdca4
JSON

In addition, inducing autophagy in an TOR-independent manner using lithium [53] or trehalose [54–56] has been shown to accelerate clearance of disease proteins in vitro [56] and protect against neurodegeneration in mouse and Drosophila models of Huntington’s disease [53,54].

a(CHEBI:"alpha,alpha-trehalose") increases bp(GO:autophagy) View Subject | View Object

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Annotations
MeSH
Huntington Disease

a(CHEBI:"alpha,alpha-trehalose") decreases path(HBP:Neurodegeneration) View Subject | View Object

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Annotations
MeSH
Huntington Disease

a(CHEBI:"lithium(1+)") increases bp(GO:autophagy) View Subject | View Object

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Annotations
MeSH
Huntington Disease

a(CHEBI:"lithium(1+)") decreases path(HBP:Neurodegeneration) View Subject | View Object

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Annotations
MeSH
Huntington Disease

Evidence 11d23e013f
JSON

This role in recycling is complementary to that of the UPS, which degrades proteins to generate oligopeptides that are subsequently degraded into amino acids while replenishing the cell’s supply of free ubiquitin.

deg(a(CHEBI:oligopeptide)) increases a(CHEBI:"amino acid") View Subject | View Object

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bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases rxn(reactants(a(MESH:Proteins)), products(a(CHEBI:oligopeptide))) View Subject | View Object

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

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Evidence dbbe68fdea
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Pharmacological upregulation of autophagy can be accomplished using the drug rapamycin, which works by inhibiting TOR (target of rapamycin), a pleiotropic molecule that negatively regulates autophagy, among other functions

a(CHEBI:sirolimus) decreases act(p(HGNC:MTOR)) View Subject | View Object

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

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Evidence 138eff1c46
JSON

Indeed, treatment with rapamycin ameliorates the degenerative phenotype in a Drosophila model of SBMA, as well as in Drosophila and mouse models of Huntington’s disease [48,50,52].

a(CHEBI:sirolimus) decreases path(MESH:"Bulbo-Spinal Atrophy, X-Linked") View Subject | View Object

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a(CHEBI:sirolimus) decreases path(MESH:"Huntington Disease") View Subject | View Object

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Evidence 27b89c4132
JSON

p62 localizes to a variety of ubiquitin-positive neuropathological inclusions including Lewy bodies in Parkinson’s disease, neurofibrillary tangles in tauopathies, polyglutamine-expanded huntingtin aggregates in Huntington’s disease, and aggregates of mutant SOD1 in familial amyotrophic lateral sclerosis [85–87].

a(GO:"Lewy body") association p(HGNC:SQSTM1) View Subject | View Object

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Annotations
MeSH
Parkinson Disease

a(GO:"neurofibrillary tangle") association p(HGNC:SQSTM1) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

p(HGNC:SOD1, var("?")) association p(HGNC:SQSTM1) View Subject | View Object

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Annotations
MeSH
Amyotrophic Lateral Sclerosis

p(HGNC:SQSTM1) association a(GO:"Lewy body") View Subject | View Object

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Annotations
MeSH
Parkinson Disease

p(HGNC:SQSTM1) association a(GO:"neurofibrillary tangle") View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

p(HGNC:SQSTM1) association p(HGNC:SOD1, var("?")) View Subject | View Object

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Annotations
MeSH
Amyotrophic Lateral Sclerosis

Evidence 61c09c53a8
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It has been inferred that aggresome formation in vitro is a cytoprotective response in cultured cells since their formation correlates inversely with cell death, whereas interventions that block aggresome formation enhance cytotoxicity and slow the rate of turnover of misfolded proteins [27,64,70–72]

a(GO:aggresome) negativeCorrelation bp(GO:"cell death") View Subject | View Object

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bp(GO:"cell death") negativeCorrelation a(GO:aggresome) View Subject | View Object

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Evidence a986a31482
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In mammals, autophagosomes first fuse with endosomes and multivesicular bodies to form amphisomes, which subsequently fuse with lysosomes to create degradative vacuoles termed autolysosomes [17].

a(GO:amphisome) increases complex(a(GO:amphisome), a(GO:lysosome)) View Subject | View Object

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a(GO:autophagosome) increases complex(a(GO:"multivesicular body"), a(GO:autophagosome), a(GO:endosome)) View Subject | View Object

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

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complex(a(GO:amphisome), a(GO:lysosome)) increases a(GO:autolysosome) View Subject | View Object

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Evidence 78c1e4afb1
JSON

In Huntington’s disease, affected neurons show accumulation of huntingtin in cathepsin-D-positive vacuoles [24]. Cathepsin-D is a lysosomal protease enriched in neuronal tissues, suggesting that these are autolysosomes

a(GO:autolysosome) positiveCorrelation path(MESH:"Huntington Disease") View Subject | View Object

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path(MESH:"Huntington Disease") positiveCorrelation a(GO:autolysosome) View Subject | View Object

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Evidence f3659a0866
JSON

CLN3-related neurodegeneration appears to be a consequence of reduced autophagosome-lysosome fusion [42].

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

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Evidence 4b89d90cf2
JSON

The initial step in autophagy involves expansion of a membranous structure called the “isolation membrane” or “phagophore” that engulfs a portion of the cell; the membrane eventually fuses to form a new double-membraned structure known as an autophagosome (Figure 1).

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

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

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Evidence 6296796612
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Once formed, new autophagosomes move through a stepwise maturation process that culminates with fusion to a lysosome permitting degradation of the lumenal contents.

a(GO:autophagosome) increases bp(GO:"autophagosome-lysosome fusion") View Subject | View Object

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bp(GO:"autophagosome-lysosome fusion") increases bp(GO:"protein catabolic process") View Subject | View Object

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Evidence 707aefb119
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LC3-II staining is also used as a primary histological marker of autophagosomes.

a(GO:autophagosome) association complex(a(CHEBI:phosphatidylethanolamine), p(HGNC:MAP1LC3B)) View Subject | View Object

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complex(a(CHEBI:phosphatidylethanolamine), p(HGNC:MAP1LC3B)) association a(GO:autophagosome) View Subject | View Object

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Evidence 85537e9fef
JSON

This suggestion originates from the observed accumulation of autophagic vacuoles in neurons from affected brain regions in a number of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Creutzfeldt- Jakob disease, and many of the polyglutamine diseases [21–24].

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

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Annotations
MeSH
Neurons

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

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Annotations
MeSH
Neurons

a(GO:autophagosome) positiveCorrelation path(MESH:"Creutzfeldt-Jakob Syndrome") View Subject | View Object

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Annotations
MeSH
Neurons

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

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Annotations
MeSH
Neurons

path(MESH:"Creutzfeldt-Jakob Syndrome") positiveCorrelation a(GO:autophagosome) View Subject | View Object

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Annotations
MeSH
Neurons

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

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Annotations
MeSH
Neurons

Evidence 0465de834f
JSON

Alzheimer’s disease pathology features massive accumulation of autophagic vacuoles within large swellings along dystrophic and degenerating neurites in neocortical and hippocampal pyramidal neurons [21].

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

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Annotations
MeSH
Hippocampus
MeSH
Neocortex
MeSH
Neurites
MeSH
Pyramidal Cells

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

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MeSH
Hippocampus
MeSH
Neocortex
MeSH
Neurites
MeSH
Pyramidal Cells

Evidence e4fc126420
JSON

The consequences of impaired lysosome function, for example, may be observed in cathepsin D knockout mice and Drosophila melanogaster cathepsin D mutants which show neurodegeneration and associated accumulation of autophagosomes and lysosomes [33–35].

a(GO:autophagosome) negativeCorrelation p(HGNC:CTSD) View Subject | View Object

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a(GO:lysosome) negativeCorrelation p(HGNC:CTSD) View Subject | View Object

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p(HGNC:CTSD) decreases path(HBP:Neurodegeneration) View Subject | View Object

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p(HGNC:CTSD) negativeCorrelation a(GO:lysosome) View Subject | View Object

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p(HGNC:CTSD) negativeCorrelation a(GO:autophagosome) View Subject | View Object

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Evidence c57c07fe66
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Indeed, a mouse model of distal-SBMA that expresses mutant p150/dynactin is characterized by accumulation of ubiquitin-positive aggregates and autophagic vacuoles in affected neurons [49].

a(GO:autophagosome) positiveCorrelation p(HGNC:DCTN1, var("?")) View Subject | View Object

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p(HGNC:DCTN1, var("?")) positiveCorrelation a(GO:autophagosome) View Subject | View Object

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Evidence c1d9fc9398
JSON

Indeed, primary lysosomal dysfunction in inherited congenital “lysosomal storage disorders” has long been recognized to cause severe neurodegenerative phenotypes characterized pathologically by accumulations of lysosomes and autophagic vacuoles [38]

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

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act(a(GO:lysosome)) increases a(GO:autophagosome) View Subject | View Object

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

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Evidence 9f5cad46a5
JSON

For example, the neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of inherited, neurodegenerative disorders with onset ranging from infancy to late adulthood that are caused by a variety of defects in lysosomal function.

act(a(GO:lysosome)) negativeCorrelation path(MESH:"Neuronal Ceroid-Lipofuscinoses") View Subject | View Object

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path(MESH:"Neuronal Ceroid-Lipofuscinoses") negativeCorrelation act(a(GO:lysosome)) View Subject | View Object

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Evidence 3763369575
JSON

Microtubule-based vesicular trafficking is essential for delivery of autophagosomes to lysosomes and subsequent fusion [46], and impaired dynein-mediated trafficking is associated with impaired autophagosome/ lysosome fusion and reduced protein turnover [47,48].

a(GO:microtubule) increases bp(GO:"autophagosome-lysosome fusion") View Subject | View Object

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a(MESH:Dyneins) increases bp(GO:"autophagosome-lysosome fusion") View Subject | View Object

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Evidence aac5be9801
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The substrate-chaperone complex is then targeted to the lysosome by binding to lysosome-associated membrane protein 2A (LAMP-2A) which carries out receptor-mediated translocation of the substrate into the lysosome for degradation [11,13]

tloc(a(MESH:Proteins), fromLoc(GO:intracellular), toLoc(GO:lysosome)) increases deg(a(MESH:Proteins)) View Subject | View Object

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p(HGNC:HSPA8) increases complex(a(MESH:Proteins), p(HGNC:HSPA8)) View Subject | View Object

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p(HGNC:LAMP2) increases tloc(a(MESH:Proteins), fromLoc(GO:intracellular), toLoc(GO:lysosome)) View Subject | View Object

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Evidence 2cc67725d7
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HDAC6 activity was also reported to regulate chaperone expression in response to heat shock by deacetylating Hsp90 leading to release and activation of the transcription factor HSF-1 [79].

bp(GO:"Hsp90 deacetylation") increases act(p(HGNC:HSF1)) View Subject | View Object

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p(HGNC:HDAC6) increases bp(GO:"Hsp90 deacetylation") View Subject | View Object

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p(HGNC:HDAC6) regulates complex(GO:"chaperone complex") View Subject | View Object

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Evidence e328b63310
JSON

Recent advances have demonstrated that autophagy also serves a surprisingly diverse array of additional functions, including organelle clearance, antigen presentation, elimination of microbes, as well as regulation of development and cell death [9].

bp(GO:"antigen processing and presentation") association bp(GO:autophagy) View Subject | View Object

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

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bp(GO:autophagy) association bp(GO:"antigen processing and presentation") View Subject | View Object

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

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bp(GO:autophagy) regulates bp(GO:"cell death") View Subject | View Object

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Evidence d35587bb84
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Several lines of evidence suggest that there is an impairment of autophagy resulting from impaired autophagosome-lysosome fusion combined with decreasing efficiency of the lysosomal system [60].

bp(GO:"autophagosome-lysosome fusion") increases bp(GO:autophagy) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

Evidence c055cc7135
JSON

Considering the importance of protein catabolism in maintaining cell homeostasis, it is not surprising that dysregulation of protein turnover is associated with myriad disease states such as cancer and neurodegeneration [5].

bp(GO:"cellular protein catabolic process") regulates bp(GO:"cellular homeostasis") View Subject | View Object

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bp(GO:"cellular protein catabolic process") negativeCorrelation path(MESH:Neoplasms) View Subject | View Object

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

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

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path(MESH:Neoplasms) negativeCorrelation bp(GO:"cellular protein catabolic process") View Subject | View Object

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Evidence fae4519148
JSON

Cellular stresses such as polyQ expression, proteasome impairment, oxidative stress, and increased misfolded protein burden activate transcription and translation of p62, suggesting that it functions broadly in stress situations [83,84]

bp(GO:"cellular response to stress") increases p(HGNC:SQSTM1) View Subject | View Object

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bp(GO:"response to oxidative stress") increases p(HGNC:SQSTM1) View Subject | View Object

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act(complex(GO:"proteasome complex")) decreases p(HGNC:SQSTM1) View Subject | View Object

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p(MESH:Proteins, pmod(HBP:misfolding)) increases p(HGNC:SQSTM1) View Subject | View Object

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Evidence 48545d4a0a
JSON

Microautophagy consists of direct engulfment of small volumes of cytosol by lysosomes [10], whereas chaperone-mediated autophagy (CMA) involves selective, receptor-mediated translocation of proteins into the lysosomal lumen [11].

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

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

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Evidence 89bc46ebd7
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CMA has also been found to contribute to the degradation of α-synuclein [29].

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

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Evidence 421e0dcd8e
JSON

For example, α-synuclein is degraded at least in part by CMA [29].

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

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Evidence bd4160d3ce
JSON

The neuronal protein α-synuclein, for example, can be degraded by the UPS, macroautophagy and chaperone-mediated autophagy [26,29].

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

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

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bp(GO:macroautophagy) increases deg(p(HGNC:SNCA)) View Subject | View Object

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Evidence d4a60ca241
JSON

UPS-mediated catabolism is also essential to mainten amino acid pools in acute starvation and contributes significantly to the degradation of defective proteins [1,2,7].

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") regulates bp(GO:"amino acid homeostasis") View Subject | View Object

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

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Evidence f7e67e13f4
JSON

Indeed, experimental evidence indicates that neurodegeneration is frequently associated with impaired UPS function, although whether this is a cause or consequence of neurodegeneration is a contested issue, as is reviewed elsewhere in this special issue

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") negativeCorrelation path(HBP:Neurodegeneration) View Subject | View Object

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path(HBP:Neurodegeneration) negativeCorrelation bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

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Evidence 9430fc4aa4
JSON

In the case of α-synuclein, for example, Webb et al. concluded that soluble forms of the disease protein are efficiently degraded by the UPS, while aggregated or oligomeric α-synuclein require autophagy for clearance [26].

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

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bp(GO:autophagy) increases a(HBP:"alpha-synuclein aggregates") View Subject | View Object

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bp(GO:autophagy) increases a(HBP:"alpha-synuclein oligomers") View Subject | View Object

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Evidence be450d65df
JSON

In addition to aggresome formation, impairment of the UPS in vitro has been found to induce autophagy [63,64].

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

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

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Evidence a48098b3d1
JSON

In cells that are exposed to stressors such as starvation or UPS inhibition, Alfy relocalizes from the nuclear envelope to filamentous cytoplasmic structures that are near autophagic membranes and ubiquitinated protein inclusions, as well as within autophagosomes [77].

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") decreases tloc(p(HGNC:WDFY3), fromLoc(GO:nucleus), toLoc(GO:cytoplasm)) View Subject | View Object

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tloc(p(HGNC:WDFY3), fromLoc(GO:nucleus), toLoc(GO:cytoplasm)) increases bp(GO:"protein ubiquitination") View Subject | View Object

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path(MESH:Starvation) increases tloc(p(HGNC:WDFY3), fromLoc(GO:nucleus), toLoc(GO:cytoplasm)) View Subject | View Object

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Evidence 06b9d02500
JSON

Specifically, it is suggested that K63-linked polyubiquitin chains recruit p62 and HDAC6 providing a signal for autophagic degradation [92,93].

bp(GO:"protein K63-linked ubiquitination") increases bp(GO:autophagy) View Subject | View Object

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bp(GO:"protein K63-linked ubiquitination") increases act(p(HGNC:SQSTM1)) View Subject | View Object

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bp(GO:"protein K63-linked ubiquitination") increases act(p(HGNC:HDAC6)) View Subject | View Object

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Evidence 2d9ff93881
JSON

This view was initially challenged by the observation that monoubiquitination operates as a key signal in endocytosis, a process important for numerous cell functions including lysosomal biogenesis [62]

bp(GO:"protein monoubiquitination") increases bp(GO:endocytosis) View Subject | View Object

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bp(GO:endocytosis) increases a(GO:lysosome) View Subject | View Object

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Evidence 1c3447856e
JSON

The process of autophagy is controlled by parallel activation cascades that involve ubiquitin-like (UBL) protein modification, strikingly similar to the activation cascade that regulates the UPS (Figure 2a).

bp(GO:"protein ubiquitination") regulates bp(GO:autophagy) View Subject | View Object

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Evidence 3e1d768cdc
JSON

Autophagy, by contrast, is primarily responsible for degrading long-lived proteins and maintaining amino acid pools in the setting of chronic starvation, although its contribution to the degradation of defective proteins may equal that of the UPS.

bp(GO:autophagy) increases bp(GO:"cellular protein catabolic process") View Subject | View Object

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bp(GO:autophagy) regulates bp(GO:"amino acid homeostasis") View Subject | View Object

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Evidence a73835af47
JSON

“Autophagy”, literally “self-eating”, describes a catabolic process in which cell constituents such as organelles and proteins are delivered to the lysosomal compartment for degradation.

bp(GO:autophagy) increases tloc(a(GO:organelle), fromLoc(GO:cytoplasm), toLoc(GO:lysosome)) View Subject | View Object

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

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Annotations
MeSH
Lysosomes

bp(GO:autophagy) increases tloc(a(MESH:Proteins), fromLoc(GO:cytoplasm), toLoc(GO:lysosome)) View Subject | View Object

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

Appears in Networks:
Annotations
MeSH
Lysosomes

Evidence 283940bc75
JSON

Autophagy is an evolutionarily conserved process whose primary task in lower organisms is the maintenance of metabolic homeostasis in the face of changing nutrient availability [8].

bp(GO:autophagy) regulates bp(GO:"metabolic process") View Subject | View Object

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Evidence b12d4317bf
JSON

It has also been suggested that autophagy plays a role in the initiation or progression of some neurodegenerative diseases [20].

bp(GO:autophagy) association path(MESH:"Neurodegenerative Diseases") View Subject | View Object

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path(MESH:"Neurodegenerative Diseases") association bp(GO:autophagy) View Subject | View Object

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Evidence 1a224c9c9d
JSON

Insight into the role of autophagy in neurodegeneration has been provided by studies indicating that: 1) some neurodegenerative disease-related proteins are degraded by autophagy, 2) impairment of autophagy promotes neurodegeneration in animal models and several human neurodegenerative diseases, and 3) manipulation of autophagy modifies phenotypes in animal models of neurodegeneration.

bp(GO:autophagy) negativeCorrelation path(MESH:"Neurodegenerative Diseases") View Subject | View Object

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path(MESH:"Neurodegenerative Diseases") negativeCorrelation bp(GO:autophagy) View Subject | View Object

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Evidence 020ab1830b
JSON

That neurodegenerative disease-causing proteins are frequently degraded by autophagy was demonstrated by a series of in vitro studies which showed that pharmacological induction or inhibition of macroautophagy alters the rate of turnover of a number of disease-related proteins including polyglutamine-expanded proteins, polyalanine-expanded proteins, as well as wild type and mutant forms of α-synuclein [25,26]

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

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bp(GO:autophagy) increases deg(p(HGNC:SNCA, var("?"))) View Subject | View Object

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Evidence fa31cfd80e
JSON

It is becoming increasingly evident that the autophagy-lysosomal system is essential to neuronal homeostasis, and may in some settings be neuroprotective

bp(GO:autophagy) regulates bp(GO:"neuron cellular homeostasis") View Subject | View Object

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

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Evidence a44e362d88
JSON

Similarly, in transgenic mice expressing amyloid precursor protein, a mouse model of Alzheimer’s disease, genetic inhibition of autophagy by heterozygous depletion of beclin-1 results in enhancement of neurodegeneration [51].

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

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Annotations
MeSH
Alzheimer Disease

Evidence 98d74948e9
JSON

For example, in a Drosophila model of X-linked spinobulbar muscular atrophy (SBMA), a polyglutamine disease, degeneration was strongly enhanced by genetic inhibition of autophagy [50].

bp(GO:autophagy) negativeCorrelation path(MESH:"Bulbo-Spinal Atrophy, X-Linked") View Subject | View Object

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path(MESH:"Bulbo-Spinal Atrophy, X-Linked") negativeCorrelation bp(GO:autophagy) View Subject | View Object

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Evidence 47671d96e6
JSON

It has now been established that clearance of misfolded proteins from aggresomes is mediated at least in part by autophagy, implicating this pathway as a compensatory mechanism for degrading misfolded proteins when the proteasome is impaired [27,64,71,73].

bp(GO:autophagy) regulates deg(p(MESH:Proteins, pmod(HBP:misfolding))) View Subject | View Object

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Evidence aad791a967
JSON

Similar induction of autophagy is observed in response to genetic impairment of the proteasome in Drosophila [50].

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

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

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Evidence 81364b5897
JSON

These processes are distinguished from macroautophagy, in which an isolation membrane expands to engulf a portion of the cell, eventually fusing to form a new autophagic vacuole that subsequently fuses with a lysosome [12].

bp(GO:macroautophagy) increases bp(GO:"autophagosome-lysosome fusion") View Subject | View Object

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Evidence 0ef4f66fe3
JSON

There have been fewer efforts to manipulate UPS function for therapeutic benefit in neurodegenerative disease, but it was recently shown that use of a proteasome activator enhanced survival in an in vitro model of Huntington’s disease [58], suggesting that augmenting other routes of protein degradation may also provide neuroprotection.

act(complex(GO:"proteasome complex")) decreases path(HBP:Neurodegeneration) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Huntington Disease

Evidence 64d2ef12c0
JSON

While GABARAP and GATE-16 may also be conjugated to PE in experimental systems, at present MAP-LC3 (typically abbreviated LC3) is the only protein that is known to remain associated with the autophagosome in higher eukaryotes.

p(HGNC:MAP1LC3B) increases complex(a(GO:autophagosome), p(HGNC:MAP1LC3B)) View Subject | View Object

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p(HGNC:GABARAP) increases complex(a(CHEBI:phosphatidylethanolamine), p(HGNC:GABARAP)) View Subject | View Object

Appears in Networks:

p(HGNC:GABARAPL2) increases complex(a(CHEBI:phosphatidylethanolamine), p(HGNC:GABARAPL2)) View Subject | View Object

Appears in Networks:

Evidence 88719ed42a
JSON

LC3-I becomes conjugated to PE to form “LC3-II” and thereby covalently associates with the phagophore

p(HGNC:MAP1LC3B) increases complex(a(CHEBI:phosphatidylethanolamine), p(HGNC:MAP1LC3B)) View Subject | View Object

Appears in Networks:

complex(a(CHEBI:phosphatidylethanolamine), p(HGNC:MAP1LC3B)) increases complex(a(CHEBI:phosphatidylethanolamine), a(GO:phagophore), p(HGNC:MAP1LC3B)) View Subject | View Object

Appears in Networks:

Evidence 649169a8a6
JSON

CMA is a process in which proteins harboring a pentapeptide motif related to the sequence KFERQ are specifically recognized by a cytosolic chaperone, the heat shock cognate protein of 70 kDa (hsc70).

p(HGNC:HSPA8) increases complex(a(MESH:Proteins), p(HGNC:HSPA8)) View Subject | View Object

Appears in Networks:

Evidence 8bd800c242
JSON

These Atg12-Atg5 conjugates are further cross-linked to Atg16 to form a large (~350 kDa) multimeric complex, which has been thought to act as a structural support for membrane expansion [15].

complex(p(HGNC:ATG12), p(HGNC:ATG16L1), p(HGNC:ATG5)) increases a(GO:phagophore) View Subject | View Object

Appears in Networks:

complex(p(HGNC:ATG12), p(HGNC:ATG5)) increases complex(p(HGNC:ATG12), p(HGNC:ATG16L1), p(HGNC:ATG5)) View Subject | View Object

Appears in Networks:

Evidence 6f3b42e1bb
JSON

As mentioned above, dramatic illustration of the interrelatedness of the UPS and autophagy was provided by characterizations of mice with conditional knockout of the essential autophagy genes Atg5 or Atg7 in the central nervous system, which resulted in neurodegeneration with accumulation of ubiquitin-positive pathology [36,37].

p(HGNC:ATG5) decreases path(HBP:Neurodegeneration) View Subject | View Object

Appears in Networks:

p(HGNC:ATG7) decreases path(HBP:Neurodegeneration) View Subject | View Object

Appears in Networks:

Evidence 2be2b8594e
JSON

More recent work has demonstrated that the Atg12-Atg5 conjugate can function as an E3-like enzyme in the second arm of the Atg conjugation cascade to promote lipidation of Atg8 [16]

complex(p(HGNC:ATG12), p(HGNC:ATG5)) increases p(HGNC:GABARAPL2, pmod(GO:"protein lipidation")) View Subject | View Object

Appears in Networks:

Evidence 3f84f29595
JSON

In a second arm of the Atg conjugation system, Atg4 cleaves the UBL protein Atg8 to promote interaction with Atg7.

p(HGNC:ATG4A) increases p(HGNC:GABARAPL2, frag("?")) View Subject | View Object

Appears in Networks:

p(HGNC:ATG4A) increases complex(p(HGNC:ATG4A), p(HGNC:ATG7)) View Subject | View Object

Appears in Networks:

Evidence 78602b43ef
JSON

Similar results have recently been observed in vitro using the proteasome inhibitor lactacystin, as pre-treatment with rapamycin attenuates lactacystin-induced apoptosis and reduces lactacystin-induced ubiquitinated protein aggregation [74].

composite(a(CHEBI:lactacystin), a(CHEBI:sirolimus)) decreases bp(GO:"apoptotic process") View Subject | View Object

Appears in Networks:

composite(a(CHEBI:lactacystin), a(CHEBI:sirolimus)) decreases p(MESH:Proteins, pmod(Ub)) View Subject | View Object

Appears in Networks:

Evidence 13f58393d3
JSON

In the first arm of the Atg conjugation system, phagophore membrane elongation is triggered through the sequential action of an E1-like protein (Atg7) and an E2-like protein (Atg10) leading to an isopeptide linkage between the C-terminal glycine the UBL protein Atg12 and a lysine residue of Atg5 (Figure 2b).

composite(p(HGNC:ATG10), p(HGNC:ATG7)) increases complex(p(HGNC:ATG12), p(HGNC:ATG5)) View Subject | View Object

Appears in Networks:

composite(p(HGNC:ATG10), p(HGNC:ATG7)) increases a(GO:phagophore) View Subject | View Object

Appears in Networks:

Evidence c47363192f
JSON

Atg8 is then conjugated with the phospholipid phosphotidylethanolamine (PE) by the concerted action of the E2-like Atg3 and the E3-like Atg12-Atg5 conjugate

composite(p(HGNC:ATG12), p(HGNC:ATG3), p(HGNC:ATG5)) increases complex(a(CHEBI:phosphatidylethanolamine), p(HGNC:GABARAPL2, frag("?"))) View Subject | View Object

Appears in Networks:

Evidence a66c26d161
JSON

Diseasecausing mutations in ATP13A2 result in protein retention in the endoplasmic reticulum and enhanced proteasomal degradation, suggesting that neurodegeneration could be caused by overwhelming the UPS and/or loss of function in lysosomal protein degradation [39].

p(HGNC:ATP13A2, var("?")) increases bp(GO:"proteasomal protein catabolic process") View Subject | View Object

Appears in Networks:

p(HGNC:ATP13A2, var("?")) increases path(HBP:Neurodegeneration) View Subject | View Object

Appears in Networks:

Evidence 394f7ba338
JSON

Mutations in CLN3, a transmembrane protein that localizes to the late endosomal/lysosomal membrane, cause a form of NCL

p(HGNC:CLN3, var("?")) increases path(MESH:"Neuronal Ceroid-Lipofuscinoses") View Subject | View Object

Appears in Networks:

Evidence 6e124e16e5
JSON

Although the mechanism whereby autophagy and UPS function are coordinated is little understood, several regulators have emerged as important players in mediating this crosstalk, including histone deacetylase 6 (HDAC6) [50,64,75], p62/sequestosome 1 (p62) [76], and the FYVE-domain containing protein Alfy [77]; notably, these proteins have all been found to regulate or be essential for aggresome formation

p(HGNC:HDAC6) regulates bp(GO:autophagy) View Subject | View Object

Appears in Networks:

p(HGNC:HDAC6) regulates bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

p(HGNC:HDAC6) regulates a(GO:aggresome) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

p(HGNC:SQSTM1) regulates bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

p(HGNC:SQSTM1) regulates a(GO:aggresome) View Subject | View Object

Appears in Networks:

p(HGNC:WDFY3) regulates bp(GO:autophagy) View Subject | View Object

Appears in Networks:

p(HGNC:WDFY3) regulates bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

p(HGNC:WDFY3) regulates a(GO:aggresome) View Subject | View Object

Appears in Networks:

Evidence 7ffaa01b11
JSON

Recent models propose that p62 and HDAC6 function analogously to facilitate autophagic degradation of proteins that display specific polyubiquitin topology.

p(HGNC:HDAC6) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

p(HGNC:HDAC6) increases bp(GO:"ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

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

Appears in Networks:

p(HGNC:SQSTM1) increases bp(GO:"ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

Evidence 84aa75dc0b
JSON

HDAC6 activity appears to be important for trafficking ubiquitinated proteins and lysosomes in vitro and this has led to the suggestion that HDAC6 coordinates delivery of substrates to autophagic machinery [64,70,78].

p(HGNC:HDAC6) increases tloc(p(MESH:Proteins, pmod(Ub)), fromLoc(GO:cytoplasm), toLoc(GO:lysosome)) View Subject | View Object

Appears in Networks:

Evidence b2c3b76b86
JSON

Rab7 participates in trafficking autophagosomes and fusion with lysosomes and disease-causing mutations are predicted to impair this process [43–45].

p(HGNC:RAB7A) increases bp(GO:"autophagosome-lysosome fusion") View Subject | View Object

Appears in Networks:

p(HGNC:RAB7A, var("?")) decreases bp(GO:"autophagosome-lysosome fusion") View Subject | View Object

Appears in Networks:

Evidence e80e43e50d
JSON

Mutations in α-synuclein that are causative of familial Parkinson’s disease are poorly transferred to the lysosomal lumen and accumulate on the lysosomal surface, resulting in blockade of receptor-mediated translocation.

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

Appears in Networks:

p(HGNC:SNCA, var("?")) decreases tloc(p(HGNC:SNCA, var("?")), fromLoc(GO:cytoplasm), toLoc(GO:"lysosomal lumen")) View Subject | View Object

Appears in Networks:

Evidence 10f9f3c42c
JSON

Thus, it has been suggested that p62 provides a key link between autophagy and the UPS by facilitating autophagic degradation of ubiquitinated proteins.

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

Appears in Networks:

p(HGNC:SQSTM1) increases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

p(HGNC:SQSTM1) increases deg(p(MESH:Proteins, pmod(Ub))) View Subject | View Object

Appears in Networks:

Evidence 22534a00ac
JSON

This model is consistent with an older study showing that inactivation of the ubiquitin-activating enzyme E1 leads to a defect in autolysosomal degradation and to an absence of ubiquitin-positive proteins within lysosomes [68].

p(HGNC:UBA1) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

p(HGNC:UBA1) increases bp(GO:"protein ubiquitination") View Subject | View Object

Appears in Networks:

Evidence 4b01de82e5
JSON

Mutations in blue cheese, the Drosophila homology of human Alfy, lead to reduced longevity and the accumulation of ubiquitinated neural aggregates, suggesting that its role in autophagic degradation may be involved in the clearance of ubiquitin aggregates [77,94]

p(HGNC:WDFY3) increases bp(GO:"ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

Evidence 25ed961fad
JSON

Many neurodegenerative diseases are characterized by accumulation of misfolded protein deposits in affected brain regions, suggesting a failure in the cell’s degradative capacity [19].

p(MESH:Proteins, pmod(HBP:misfolding)) positiveCorrelation path(MESH:"Neurodegenerative Diseases") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Neurodegenerative Diseases") positiveCorrelation p(MESH:Proteins, pmod(HBP:misfolding)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

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.