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bp(GO:autophagy)

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Entity

Name
autophagy
Namespace
go
Namespace Version
20180921
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/go-names.belns

Appears in Networks 24

The Ubiquitin Proteasome System in Neurodegenerative Diseases: Sometimes the Chicken, Sometimes the Egg v1.0.0

The Biology of Proteostasis in Aging and Disease v1.0.0

Alpha-synuclein oligomers: a new hope v1.0.0

Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing v1.0.0

Tau clearance mechanisms and their possible role in the pathogenesis of Alzheimer disease v1.0.0

Tau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system. v1.0.0

Molecular chaperones and regulation of tau quality control: strategies for drug discovery in tauopathies v1.0.0

Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies v1.0.0

Clearance systems in the brain-implications for Alzheimer disease. v1.0.1

Clearance of Amyloid Beta and Tau in Alzheimer’s Disease:from Mechanisms to Therapy v1.0.1

Tau Modifications v1.9.5

Tau Modifications Sections of NESTOR

Activation and regulation of the inflammasomes v1.0.0

Oxidative stress in health and disease: The therapeutic potential of Nrf2 activation v1.0.0

Alzheimer’s disease and the autophagic-lysosomal system v1.0.0

The Ubiquitin–Proteasome System and the Autophagic–Lysosomal System in Alzheimer Disease v1.0.0

Molecular Chaperone Functions in Protein Folding and Proteostasis v1.0.0

Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection v1.0.0

Molecular chaperones and proteostasis regulation during redox imbalance v1.0.0

Pathological missorting of endogenous MAPT/Tau in neurons caused by failure of protein degradation systems v1.0.0

Carboxy terminus heat shock protein 70 interacting protein reduces tau-associated degenerative changes v1.0.0

Upstream regulators and downstream effectors of NF-κBinAlzheimer's disease v1.0.0

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders v1.0.0

Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome v1.0.0

Pathological missorting of endogenous MAPT/Tau in neurons caused by failure of protein degradation systems v1.0.1

In-Edges 138

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

Another modulator of A-LS implicated in AD pathology is transcription factor EB (TFEB), a master regulator of lysosome biogenesis PubMed:29758300

Appears in Networks:

a(PUBCHEM:877863) increases bp(GO:autophagy) View Subject | View Object

A screen for autophagy inducers in yeast identified the molecules SMER-10, -18, and -28 as TOR-independent activators of autophagy (146). PubMed:25784053

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Annotations
Cell Ontology (CL)
motor neuron

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

Neuronal autophagy has been found to occur following chronic, low-grade proteasomal inhibition in cultured neuroblastoma cells (Ding et al., 2003) and may reflect activation of the lysosomal system as cells try to protect themselves during stress (Larsen and Sulzer, 2002). PubMed:14556719

Appears in Networks:
Annotations
MeSH
Neurons

a(CHEBI:chloroquine) decreases bp(GO:autophagy) View Subject | View Object

Reduced levels of lipofuscin, LC3, and p62 have been observed in motor neurons of SOD1(G85R) mice (92). Treatment with the autophagy inhibitor chloroquine restored lipofuscin, LC3, and p62 levels in motor neurons, suggesting that mutant SOD1 causes hyperactive autophagy in mice (92). PubMed:25784053

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Cell Ontology (CL)
motor neuron

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

An in silico screen based on the structure of 10-NCP, an Akt inhibitor that potently induces autophagy (144), identified the molecules FPZ and MTM as potent activators of autophagic flux and clearance of TDP-43 in mammalian cells (145). PubMed:25784053

Appears in Networks:
Annotations
Cell Ontology (CL)
motor neuron

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

An in silico screen based on the structure of 10-NCP, an Akt inhibitor that potently induces autophagy (144), identified the molecules FPZ and MTM as potent activators of autophagic flux and clearance of TDP-43 in mammalian cells (145). PubMed:25784053

Appears in Networks:
Annotations
Cell Ontology (CL)
motor neuron

a(PUBCHEM:10521421) increases bp(GO:autophagy) View Subject | View Object

An in silico screen based on the structure of 10-NCP, an Akt inhibitor that potently induces autophagy (144), identified the molecules FPZ and MTM as potent activators of autophagic flux and clearance of TDP-43 in mammalian cells (145). PubMed:25784053

Appears in Networks:
Annotations
Cell Ontology (CL)
motor neuron

a(PUBCHEM:1560402) increases bp(GO:autophagy) View Subject | View Object

A screen for autophagy inducers in yeast identified the molecules SMER-10, -18, and -28 as TOR-independent activators of autophagy (146). PubMed:25784053

Appears in Networks:
Annotations
Cell Ontology (CL)
motor neuron

a(PUBCHEM:799645) increases bp(GO:autophagy) View Subject | View Object

A screen for autophagy inducers in yeast identified the molecules SMER-10, -18, and -28 as TOR-independent activators of autophagy (146). PubMed:25784053

Appears in Networks:
Annotations
Cell Ontology (CL)
motor neuron

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

In contrast, α-synuclein overexpression impairs autophagy in mammalian cells and mice through reduced expression of RAB1A, thereby inhibiting autophagosome formation (88). PubMed:25784053

Appears in Networks:

p(HGNC:SOD1, var("p.Gly576Arg")) increases bp(GO:autophagy) View Subject | View Object

Reduced levels of lipofuscin, LC3, and p62 have been observed in motor neurons of SOD1(G85R) mice (92). Treatment with the autophagy inhibitor chloroquine restored lipofuscin, LC3, and p62 levels in motor neurons, suggesting that mutant SOD1 causes hyperactive autophagy in mice (92). PubMed:25784053

Appears in Networks:
Annotations
Cell Ontology (CL)
motor neuron

path(MESH:"Amyotrophic Lateral Sclerosis") increases bp(GO:autophagy) View Subject | View Object

In contrast to findings in HD, AD, and PD, a recent study has suggested that autophagy is enhanced in ALS mice. PubMed:25784053

Appears in Networks:

p(HGNC:BCL2) decreases bp(GO:autophagy) View Subject | View Object

For instance, c-Jun NH 2-terminal kinase 1 (JNK1) may induce autophagy by phosphorylating Bcl-2 or Bim and abolishing their inhibitory effects on autophagy (Luo et al., 2012; Wei et al., 2008). PubMed:23528736

Appears in Networks:

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

This mechanism may be involved in its promotion of autophagy, reduction in cel- lular levels of α-synuclein, SOD1, Htt and tau 126 , ame- lioration of motor function in a P301L mouse model of tauopathy 127 and slowing of disease progression in SOD1 mice 128 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"methylene blue") increases bp(GO:autophagy) View Subject | View Object

For example, methylene blue coun- ters tau oligomerization and promotes autophagy 101,102 (Supplementary Table 4). PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

a(CHEBI:"methylene blue") increases bp(GO:autophagy) View Subject | View Object

Other compounds that act through AMPK acti- vation include the antiaggregant methylene blue (Supplementary Box 1), which elevated levels of beclin  1, p62 and LC3, induced autophagy and suppressed tau in organotypic neuronal cultures and a mouse model of FTD 101,102 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

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

Calpeptin, a cell-permeable calpain inhibitor, can also reduce Htt proteinopathy via induction of autophagy 103,105 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

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

Indeed, clonidine and rilmenidine, two G i /G o -coupled α 2 -adrenergic receptor and imidazoline 1 receptor agonists, stimulate autophagy and cleared Htt in cellular 103 and animal models of HD 104 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

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

In addition, calcitriol (the active metabolite of vitamin D 3 ) elicited AMPK-dependent autophagy in a neurochemical lesion-induced model of PD 129. PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Parkinson Disease

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

Indeed, clonidine and rilmenidine, two G i /G o -coupled α 2 -adrenergic receptor and imidazoline 1 receptor agonists, stimulate autophagy and cleared Htt in cellular 103 and animal models of HD 104 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

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

The antidiabetic drug metformin, a prototypical activator of AMPK, induced autophagy and increased longevity in mice 116 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

p(HGNC:BCL2L11) decreases bp(GO:autophagy) View Subject | View Object

For instance, c-Jun NH 2-terminal kinase 1 (JNK1) may induce autophagy by phosphorylating Bcl-2 or Bim and abolishing their inhibitory effects on autophagy (Luo et al., 2012; Wei et al., 2008). PubMed:23528736

Appears in Networks:

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

Selenium deficits have been linked to AD, and thus it is interesting that seleno- methionine boosted ALN flux, from AMPK recruit- ment through autophagosome formation to lysosomal degradation, in the 3×Tg AD mouse model 112 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

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

Enhancing auto- phagy with rapamycin reduced levels of α-synuclein, FUS and Htt 130–132 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

g(HGNC:PSEN1, var("?")) negativeCorrelation bp(GO:autophagy) View Subject | View Object

Fourth, genetic mutations and anomalies of presenilin 1, a dominant negative gene linked to AD, are associated with reduced lysosomal v-ATPase-mediated acidifica- tion 40,63 , a compromised ALN and deficient mitophagy 64 . PubMed:30116051

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Annotations
MeSH
Alzheimer Disease

act(p(FPLX:AMPK)) increases bp(GO:autophagy) View Subject | View Object

The aminoimidazole derivative 5-aminoimidazole- 4-carboxamide ribonucleotide (AICAR) undergoes intra- cellular transformation to an AMP analogue that triggers AMPK-mediated autophagy 21,108 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

act(p(FPLX:AMPK)) increases bp(GO:autophagy) View Subject | View Object

The di-glucose derivative trehalose inhibits the sol- ute carrier 2A (SLC2A) family of glucose transporters to promote AMPK-induced autophagy and reduce neurotoxic protein load, although it also exerts other actions downstream in the ALN 4,120 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

p(HGNC:C9orf72, var("?")) decreases bp(GO:autophagy) View Subject | View Object

Mutations in C9ORF72 (the most prevalent risk gene for familial ALS and FTD) are likewise linked to disruption of the ALN, including interference with dynactin–dynein coordinated transport of autophagosomes along axons of motor neurons to the perikarya 82,88 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Amyotrophic Lateral Sclerosis

p(HGNC:CAPN1) decreases bp(GO:autophagy) View Subject | View Object

Genetic knockdown of calpain 1 or calpain 2 or overexpression of their endogenous inhibitor, calpastatin, increased autophagy and cleared aggregates in SK-N-SH cells overexpressing a mutant form of Htt 103 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

p(HGNC:CAPN2) decreases bp(GO:autophagy) View Subject | View Object

Genetic knockdown of calpain 1 or calpain 2 or overexpression of their endogenous inhibitor, calpastatin, increased autophagy and cleared aggregates in SK-N-SH cells overexpressing a mutant form of Htt 103 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

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

Genetic knockdown of calpain 1 or calpain 2 or overexpression of their endogenous inhibitor, calpastatin, increased autophagy and cleared aggregates in SK-N-SH cells overexpressing a mutant form of Htt 103 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

p(HGNC:GBA, var("?")) decreases bp(GO:autophagy) View Subject | View Object

Fourth, homozygous mutations of lyso- somal β-glucocerebrosidase (βGCase; also known as GBA) provoke the LSD Gaucher disease, which is linked to decreased ALN flux, α-synuclein accumulation and a fivefold increase in risk of PD 43 (Supplementary Box 1). PubMed:30116051

Appears in Networks:
Annotations
MeSH
Parkinson Disease

p(HGNC:HTT, var("?")) decreases bp(GO:autophagy) View Subject | View Object

Mutant Htt is cleared by autophagy, but it compromises the ALN because of decreased cargo load- ing and impaired autophagosome formation and trans- port 55,56,68,92 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

p(HGNC:LRRK2, var("?")) decreases bp(GO:autophagy) View Subject | View Object

Some of these lead to an impairment of the ALN owing to reduced activation of beclin 1; another repercussion may be altered process- ing of APP, providing an unexpected link to AD 69,71–73 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Parkinson Disease

deg(p(HGNC:MAPT)) association bp(GO:autophagy) View Subject | View Object

PSA has been shown to be involved in the induction of autophagy and specifically the formation of autophagosomes, in a model of overexpressed mutant huntingtin (32). Thus, the in vivo effects of PSA on promoting tau clearance may relate to its ability to modulate the key clearance pathway for abnormal and aggregated proteins (to be described in more detail below). PubMed:24027553

Appears in Networks:
Annotations
MeSH
Huntington Disease
Text Location
Review

p(HGNC:NPEPPS) association bp(GO:autophagy) View Subject | View Object

PSA has been shown to be involved in the induction of autophagy and specifically the formation of autophagosomes, in a model of overexpressed mutant huntingtin (32). Thus, the in vivo effects of PSA on promoting tau clearance may relate to its ability to modulate the key clearance pathway for abnormal and aggregated proteins (to be described in more detail below). PubMed:24027553

Appears in Networks:
Annotations
MeSH
Huntington Disease
Text Location
Review

p(HGNC:MAPK8) increases bp(GO:autophagy) View Subject | View Object

For instance, c-Jun NH 2-terminal kinase 1 (JNK1) may induce autophagy by phosphorylating Bcl-2 or Bim and abolishing their inhibitory effects on autophagy (Luo et al., 2012; Wei et al., 2008). PubMed:23528736

Appears in Networks:

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

and lithium (Shimada et al., 2012) in human tau over-expressing Tg mice induced autophagy, which is accompanied by the reduced levels of pathological tau and NFT formation in tauopathy model mice. PubMed:23528736

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

Trehalose, an natural disaccharide and mTOR-independent activator of autophagy (Sarkar et al., 2007), showed an effect on neuronal survival, reducing the level of tau aggregates in the brain of human tauopathy model mice (Kruger et al., 2011; Rodriguez-Navarro et al., 2010; Schaeffer et al., 2012). PubMed:23528736

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a(CHEBI:"methylene blue") increases bp(GO:autophagy) View Subject | View Object

Methylene blue, which has been known to directly inhibit tau aggregation, is also capable to induce autophagy and reduce total and phospho-tau levels with improved cognitive performance in tau transgenic mice by oral administration (Congdon et al., 2012). PubMed:23528736

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bp(GO:"response to oxidative stress") increases bp(GO:autophagy) View Subject | View Object

Oxidative stress also upregulates autophagy induction, which limits the production of reactive oxygen species from dysfunctional mitochondria. PubMed:23528736

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

Aging, a major risk factor for AD, affects both the UPS and autophagy. PubMed:23528736

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p(FPLX:AMPK) increases bp(GO:autophagy) View Subject | View Object

The mammalian target of rapamycin (mTOR) kinase negatively modulates autophagy by phosphorylating Atg1, an autophagy initiating factor, while adenosine monophosphate-activated protein kinase (AMPK), a major sensor for the cellular energy status, activates autophagy through inhibiting mTOR signaling as well as by direct phosphorylation of Atg1 (Egan et al., 2011; Kim et al., 2011). Increased mTOR activity results in autophagy downregulation and tau accumulation. PubMed:23528736

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p(FPLX:mTORC1) decreases bp(GO:autophagy) View Subject | View Object

The mammalian target of rapamycin (mTOR) kinase negatively modulates autophagy by phosphorylating Atg1, an autophagy initiating factor, while adenosine monophosphate-activated protein kinase (AMPK), a major sensor for the cellular energy status, activates autophagy through inhibiting mTOR signaling as well as by direct phosphorylation of Atg1 (Egan et al., 2011; Kim et al., 2011). Increased mTOR activity results in autophagy downregulation and tau accumulation. PubMed:23528736

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p(HGNC:ULK1) increases bp(GO:autophagy) View Subject | View Object

The mammalian target of rapamycin (mTOR) kinase negatively modulates autophagy by phosphorylating Atg1, an autophagy initiating factor, while adenosine monophosphate-activated protein kinase (AMPK), a major sensor for the cellular energy status, activates autophagy through inhibiting mTOR signaling as well as by direct phosphorylation of Atg1 (Egan et al., 2011; Kim et al., 2011). Increased mTOR activity results in autophagy downregulation and tau accumulation. PubMed:23528736

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a(MESH:"Heat-Shock Proteins") increases bp(GO:autophagy) View Subject | View Object

Importantly, the Hsps are also critical at the end of a protein’s life, as they facilitate turnover by the proteasome system and the clearance of proteotoxic aggregates by autophagy [53] PubMed:21882945

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p(HGNC:HSPB1) increases bp(GO:autophagy) View Subject | View Object

During protein quality control, Hsp70, Hsp90 and Hsp27 (and their co-chaperones) often work in concert. If prolonged misfolding is detected, the chaperones shuttle the protein to a degradation endpoint, such as the proteasome or autophagy PubMed:21882945

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p(FPLX:HSP90) increases bp(GO:autophagy) View Subject | View Object

During protein quality control, Hsp70, Hsp90 and Hsp27 (and their co-chaperones) often work in concert. If prolonged misfolding is detected, the chaperones shuttle the protein to a degradation endpoint, such as the proteasome or autophagy PubMed:21882945

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p(INTERPRO:"Heat shock protein 70 family") increases bp(GO:autophagy) View Subject | View Object

During protein quality control, Hsp70, Hsp90 and Hsp27 (and their co-chaperones) often work in concert. If prolonged misfolding is detected, the chaperones shuttle the protein to a degradation endpoint, such as the proteasome or autophagy PubMed:21882945

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p(HGNC:MAPT) decreases bp(GO:autophagy) View Subject | View Object

An additional “knot” of tau being entangled in epigenetic landscape of neurodegeneration comes from the finding that by acting as a HDAC6 inhibitor, tau is being indirectly involved in both (dys)regulation of transcriptional activity and impairment of autophagic clearance by the ubiquitin proteasome system [81,82]. PubMed:26751493

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

Recent acknowledged drugs can improve autophagy by acting on the process of autophagy-lysosome formation and then increasing tau clearance, such as methylene blue, lithium, and trehalose (Congdon et al. 2012; Kruger et al. 2012; Shimada et al. 2012) PubMed:29626319

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

Proteasome inhibitors and trehalose increase autophagy and decrease tau content by up-regulating the expression of cochaperone BAG3 targeting tau to the autophagy pathway for degradation (Lei et al. 2015) PubMed:29626319

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

Recent acknowledged drugs can improve autophagy by acting on the process of autophagy-lysosome formation and then increasing tau clearance, such as methylene blue, lithium, and trehalose (Congdon et al. 2012; Kruger et al. 2012; Shimada et al. 2012) PubMed:29626319

Appears in Networks:

a(CHEBI:"methylene blue") increases bp(GO:autophagy) View Subject | View Object

Recent acknowledged drugs can improve autophagy by acting on the process of autophagy-lysosome formation and then increasing tau clearance, such as methylene blue, lithium, and trehalose (Congdon et al. 2012; Kruger et al. 2012; Shimada et al. 2012) PubMed:29626319

Appears in Networks:

a(CHEBI:"proteasome inhibitor") increases bp(GO:autophagy) View Subject | View Object

Proteasome inhibitors and trehalose increase autophagy and decrease tau content by up-regulating the expression of cochaperone BAG3 targeting tau to the autophagy pathway for degradation (Lei et al. 2015) PubMed:29626319

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

Wogonin, rapamycin, and temsirolimus have been considered to improve the activity of autophagy to increase Aβ clearance and inhibit tau phosphorylation via targeting mTOR signaling (Caccamo et al. 2010; Jiang et al. 2014c; Jiang et al. 2014d; Spilman et al. 2010; Zhu andWang 2015) PubMed:29626319

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

Wogonin, rapamycin, and temsirolimus have been considered to improve the activity of autophagy to increase Aβ clearance and inhibit tau phosphorylation via targeting mTOR signaling (Caccamo et al. 2010; Jiang et al. 2014c; Jiang et al. 2014d; Spilman et al. 2010; Zhu andWang 2015) PubMed:29626319

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

Wogonin, rapamycin, and temsirolimus have been considered to improve the activity of autophagy to increase Aβ clearance and inhibit tau phosphorylation via targeting mTOR signaling (Caccamo et al. 2010; Jiang et al. 2014c; Jiang et al. 2014d; Spilman et al. 2010; Zhu andWang 2015) PubMed:29626319

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p(HGNC:NPAS4) increases bp(GO:autophagy) View Subject | View Object

Neuronal PAS domain protein 4 has been found to facilitate the autophagic clearance of endogenous total and phosphorylated tau in cortical neurons of rats PubMed:29626319

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p(HGNC:PPP2CA) increases bp(GO:autophagy) View Subject | View Object

Protein phosphatase 2A agonists are reported to activate autophagy by affecting AMPK and mTORC1 signaling pathways (Magnaudeix et al. 2013) PubMed:29626319

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

For example, like Aβ, clearance of pTau/NFT also can be regulated by TFEB, which increases the activity of autophagy and lysosome (Polito et al. 2014) PubMed:29626319

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complex(p(HGNC:BAG3), p(HGNC:HSPB8)) positiveCorrelation bp(GO:autophagy) View Subject | View Object

Overexpression of the HSPB8-BAG3 complex also stimulates autophagy and facilitates the clearance of mutated aggregation-prone proteins, the accumulation of which characterizes many neurodegenerative disorders such as Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis (Seidel et al., 2011). PubMed:22020111

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

SQSTM1, induced 20-fold, encodes sequestosome-1, a participant in the autophagy pathway recently shown to be necessary to avoid premature senescence in human fibroblasts (Kang et al., 2011). PubMed:22020111

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a(CHEBI:lipid) negativeCorrelation bp(GO:autophagy) View Subject | View Object

In addition to the direct modulation of protein generation, lipids can also influence the levels of proteins through autophagic clearance; for instance, increasing lipid contents has been shown to impair autophagy [72]. PubMed:29758300

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

For instance, rapamycin, an inhibitor of the Ser/Thr protein kinase mammalian target of rapamycin (mTOR), improves cognitive function and reduces Aβ in AD mouse model by enhancing autophagic flux [23]. PubMed:29758300

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a(HBP:"Tau aggregates") association bp(GO:autophagy) View Subject | View Object

Tau aggregates can be targeted by two protein clearance pathways, the UPS and the A-LS, with the latter pathway encompassing microautophagy,CMA and macroautophagy. PubMed:29758300

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

Even early autophagic activation may become impaired due to progressively diminishing lysosomal clearance of substrates. PubMed:29758300

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

TFEB has been shown to effectively clear phosphorylated tau proteins through A-LS, resulting in ameliorated neuronal loss and neuroinflammation, as well as improved cognitive performance [89]. PubMed:29758300

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p(HGNC:BIN1) increases bp(GO:autophagy) View Subject | View Object

Suppression of BIN1 disrupts cellular trafficking of BACE1 and reduces BACE1 lysosomal degradation, leading to increased Aβ production [103]. PubMed:29758300

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p(HGNC:MAPT, pmod(Ph)) association bp(GO:autophagy) View Subject | View Object

Abnormal phosphorylation and truncation of tau are hallmarks of AD pathology and are targets of proteasome and autophagy pathways [27,44,45]. PubMed:29758300

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p(HGNC:MAPT, pmod(Ph, Ser, 262)) increases bp(GO:autophagy) View Subject | View Object

A recent study has demonstrated that activation of AMPKα1 enhances tau phosphorylation, while inhibition reduces tau phosphorylation at Ser-262, an epitope that is increased in early stages of AD, which promotes the autophagic degradation of tau [87] PubMed:29758300

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

Modulation of mTOR can influence the levels of tau, with upregulation increasing tau phosphorylation and accumulation by reducing autophagic clearance [87], and conversely, pharmacological treatment with rapamycin reducing tau levels and rescuing motor deficits in the Tau P301S mice [53] PubMed:29758300

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p(HGNC:PSEN1, var("p.Ala246Glu")) decreases bp(GO:autophagy) View Subject | View Object

PSEN1 M146L and A246E mutant cortical neurons have been shown to possess decreased activation of the CLEAR (coordinated lysosomal expression and regulation) gene network, as measured by a TFEB-driven luciferase assay, consistent with a reduction in autophagic activity [131]. PubMed:29758300

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p(HGNC:PSEN1, var("p.Met146Leu")) decreases bp(GO:autophagy) View Subject | View Object

PSEN1 M146L and A246E mutant cortical neurons have been shown to possess decreased activation of the CLEAR (coordinated lysosomal expression and regulation) gene network, as measured by a TFEB-driven luciferase assay, consistent with a reduction in autophagic activity [131]. PubMed:29758300

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

Robust AV accumulation in dystrophic neurites from biopsy tissues from patients with AD implicate a compromised state of autophagic flux PubMed:29758300

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

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. PubMed:22908190

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

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). PubMed:22908190

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

Similar autophagy pathology is observed when lysosomal proteolysis is inhibited (Ivy et al. 1984; Koike et al. 2005; Yang et al. 2008). PubMed:22908190

Appears in Networks:

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

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) PubMed:22908190

Appears in Networks:

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

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). PubMed:22908190

Appears in Networks:

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

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). PubMed:22908190

Appears in Networks:

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

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. PubMed:22908190

Appears in Networks:

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

Indeed, many recent studies suggest the involvement of autophagy in the pathogenesis of AD PubMed:22908190

Appears in Networks:

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

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. PubMed:22908190

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

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

Specifically, it is suggested that K63-linked polyubiquitin chains recruit p62 and HDAC6 providing a signal for autophagic degradation [92,93]. PubMed:18930136

Appears in Networks:

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

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]. PubMed:18930136

Appears in Networks:
Annotations
MeSH
Huntington Disease

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

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]. PubMed:18930136

Appears in Networks:
Annotations
MeSH
Huntington Disease

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

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 PubMed:18930136

Appears in Networks:

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

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). PubMed:18930136

Appears in Networks:

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

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]. PubMed:18930136

Appears in Networks:

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

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]. PubMed:18930136

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

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

In addition to aggresome formation, impairment of the UPS in vitro has been found to induce autophagy [63,64]. PubMed:18930136

Appears in Networks:

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

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). PubMed:18930136

Appears in Networks:

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

Similar induction of autophagy is observed in response to genetic impairment of the proteasome in Drosophila [50]. PubMed:18930136

Appears in Networks:

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

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 PubMed:18930136

Appears in Networks:

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

Recent models propose that p62 and HDAC6 function analogously to facilitate autophagic degradation of proteins that display specific polyubiquitin topology. PubMed:18930136

Appears in Networks:

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

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 PubMed:18930136

Appears in Networks:

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

Thus, it has been suggested that p62 provides a key link between autophagy and the UPS by facilitating autophagic degradation of ubiquitinated proteins. PubMed:18930136

Appears in Networks:

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

Recent models propose that p62 and HDAC6 function analogously to facilitate autophagic degradation of proteins that display specific polyubiquitin topology. PubMed:18930136

Appears in Networks:

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

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]. PubMed:18930136

Appears in Networks:

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

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 PubMed:18930136

Appears in Networks:

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

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]. PubMed:18930136

Appears in Networks:

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

It has also been suggested that autophagy plays a role in the initiation or progression of some neurodegenerative diseases [20]. PubMed:18930136

Appears in Networks:

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

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. PubMed:18930136

Appears in Networks:

a(CHEBI:"reactive oxygen species") regulates bp(GO:autophagy) View Subject | View Object

Specifically, ROS have been shown to regulate a wide variety of signalling pathways including anti- inflammatory responses and adaptation to hypoxia [77,78], autop- hagy [79], immune cell function [80], cellular differentiation [81], integrins [82], as well as oncogenes signalling [83]. PubMed:24563850

Appears in Networks:

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

Our previous study [23] had shown that trehalose induces autophagy in primary neurons and in an N2a cell model of tauopathy, and efficiently reduces the level of MAPT and MAPT aggregation. PubMed:30145931

Appears in Networks:
Annotations
MeSH
Neurons

a(CHEBI:"bafilomycin A1") decreases bp(GO:autophagy) View Subject | View Object

In order to determine the impact of protein degradation systems on the sorting of MAPT, we sought to suppress their activity by treating neurons on the neuritic side of the MFCs with either autophagy inhibitors, wortmannin [25] and bafilomycin A 1 [26], or with proteasomal inhibitors, epoxomicin and lactacystin [27,28]. PubMed:30145931

Appears in Networks:

a(CHEBI:wortmannin) decreases bp(GO:autophagy) View Subject | View Object

In order to determine the impact of protein degradation systems on the sorting of MAPT, we sought to suppress their activity by treating neurons on the neuritic side of the MFCs with either autophagy inhibitors, wortmannin [25] and bafilomycin A 1 [26], or with proteasomal inhibitors, epoxomicin and lactacystin [27,28]. PubMed:30145931

Appears in Networks:

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

In contrast, chlorpromazine, which is a typical antipsychotic agent, induces autophagy by inhibiting the Akt/mTOR pathway PubMed:30061532

Appears in Networks:

a(CHEBI:"reactive oxygen species") decreases bp(GO:autophagy) View Subject | View Object

Higher levels of ROS biomarkers are characteristic of AD patients in clinical and preclinical studies, resulting in the alteration of membrane proper- ties, such as fluidity, ion transport, enzyme activities, protein cross- linking, tau protein hyperphosphorylation, autophagic dysfunction and eventually neuron cell death [20]. PubMed:27288790

Appears in Networks:

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

Recently, in vitro studies on the effects of second-generation, atypical antipsychotics demonstrated that sertindole and clozapine are potent autophagy inducers in both neuronal and non-neuronal cell lines PubMed:30061532

Appears in Networks:

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

Similar to pimozide, clozapine activates the autophagy process via the AMPK–ULK1–Beclin1 pathway, as evidenced by increased levels of autophagy markers (i.e., LC3-II and Atg5–Atg12 conjugate); increased phosphorylation of AMPK and its downstream substrates, namely ULK1 and beclin1; and an increased number of autophagosomes in the frontal cortex in clozapine-treated rats PubMed:30061532

Appears in Networks:

a(CHEBI:dopamine) regulates bp(GO:autophagy) View Subject | View Object

In line with this, METH produces ultrastructural alterations reflecting dysfunctional autophagy flux, which are DA-dependent PubMed:30061532

Appears in Networks:

a(CHEBI:methamphetamine) decreases bp(GO:autophagy) View Subject | View Object

In line with this, METH produces ultrastructural alterations reflecting dysfunctional autophagy flux, which are DA-dependent PubMed:30061532

Appears in Networks:

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

Notably, high-throughput image-based screens performed by Zhang et al. (2007) [60] on a human glioblastoma H4 cell line expressing human LC3 coupled with green fluorescent protein (GFP) led us to disclose that three typical antipsychotic drugs (fluspirilene, trifluoperazine, and pimozide) are effective autophagy inducers. PubMed:30061532

Appears in Networks:

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

For instance, the increase in autophagy flux induced by pimozide occurs along with a depression of phosphorylated tau in a transgenic mouse model of AD PubMed:30061532

Appears in Networks:
Annotations
MeSH
Frontal Lobe
MeSH
Alzheimer Disease

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

Recently, in vitro studies on the effects of second-generation, atypical antipsychotics demonstrated that sertindole and clozapine are potent autophagy inducers in both neuronal and non-neuronal cell lines PubMed:30061532

Appears in Networks:

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

Noteworthy, genetic ablation of autophagy was shown to produce an extremely powerful DA release upon electrical stimuli, suggesting that autophagy is key to restrain DA release both upon basal neural activity and mostly after rapamycin-induced autophagy PubMed:30061532

Appears in Networks:

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

Notably, high-throughput image-based screens performed by Zhang et al. (2007) [60] on a human glioblastoma H4 cell line expressing human LC3 coupled with green fluorescent protein (GFP) led us to disclose that three typical antipsychotic drugs (fluspirilene, trifluoperazine, and pimozide) are effective autophagy inducers. PubMed:30061532

Appears in Networks:

a(PUBCHEM:3396) increases bp(GO:autophagy) View Subject | View Object

Notably, high-throughput image-based screens performed by Zhang et al. (2007) [60] on a human glioblastoma H4 cell line expressing human LC3 coupled with green fluorescent protein (GFP) led us to disclose that three typical antipsychotic drugs (fluspirilene, trifluoperazine, and pimozide) are effective autophagy inducers. PubMed:30061532

Appears in Networks:

bp(GO:"dopamine secretion, neurotransmission") association bp(GO:autophagy) View Subject | View Object

These findings strongly suggest that an autophagy dysfunction acts both at pre- and post-synaptic level to alter DA neurotransmission during both METH administration and schizophrenia (Figure 2) PubMed:30061532

Appears in Networks:
Annotations
MeSH
Schizophrenia

p(HGNC:ATG3) association bp(GO:autophagy) View Subject | View Object

In particular, at BA 22, the vast majority of abnormally expressed genes referred to key autophagy genes (i.e., BECN1, ULK2, ATG3), which were significantly down-regulated compared with controls PubMed:30061532

Appears in Networks:

p(HGNC:BECN1) association bp(GO:autophagy) View Subject | View Object

In particular, at BA 22, the vast majority of abnormally expressed genes referred to key autophagy genes (i.e., BECN1, ULK2, ATG3), which were significantly down-regulated compared with controls PubMed:30061532

Appears in Networks:

p(HGNC:DISC1, var("?")) decreases bp(GO:autophagy) View Subject | View Object

Therefore, disruption of DISC1 activity, due to genetic rearrangements (i.e., balanced (1;11) (q42;q14) chromosomal translocation) or missense mutations, produces schizophrenic-like behavior, which is bound to enhanced Akt activity, over-activation of mTOR signaling, and depressed autophagy PubMed:30061532

Appears in Networks:

act(p(HGNC:DRD1)) decreases bp(GO:autophagy) View Subject | View Object

This is key, because abnormal stimulation of D1R and subsequent signaling cascades were recently shown to produce an over-activation of mTOR and inhibition of the autophagy machinery PubMed:30061532

Appears in Networks:

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

Therefore, a common pathogenesis underlying all these NDDs disorders has been linked to autophagy inhibition due to mTOR hyperactivation PubMed:30061532

Appears in Networks:

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

In fact, mTOR-induced autophagy inhibition exacerbates the ultrastructural effects of METH [126,134–136], while rapamycin administration reverts both behavioral and morphological alterations induced by METH [137]. PubMed:30061532

Appears in Networks:

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

The biological implication behind an impairment of microtubule dynamics is confirmed in post-mortem schizophrenic brain samples, as well as in mouse models of schizophrenia, where mTOR-dependent autophagy dysfunction is accompanied by an altered gene expression and protein levels of the microtubule-associated protein 6 (MAP6) PubMed:30061532

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Schizophrenia

p(HGNC:ULK1, pmod(Ph)) increases bp(GO:autophagy) View Subject | View Object

In particular, pimozide provides an mTOR-independent autophagy induction, because it directly activates AMPK1, which in turn promotes autophagy through the phosphorylation of ULK1 PubMed:30061532

Appears in Networks:

p(HGNC:ULK2) association bp(GO:autophagy) View Subject | View Object

In particular, at BA 22, the vast majority of abnormally expressed genes referred to key autophagy genes (i.e., BECN1, ULK2, ATG3), which were significantly down-regulated compared with controls PubMed:30061532

Appears in Networks:

path(MESH:Hallucinations) negativeCorrelation bp(GO:autophagy) View Subject | View Object

A few months later, another transcriptomic study reported a BA 22-specific down-regulation in several autophagy-related genes, thus strengthening the link between impaired autophagy and schizophrenia positive symptoms PubMed:30061532

Appears in Networks:

path(MESH:Schizophrenia) negativeCorrelation bp(GO:autophagy) View Subject | View Object

Remarkably, the identification of rare genetic variants of ULK1 in a cohort of schizophrenic patients by means of exome sequence analysis strengthens the idea of a key role of both disrupted mTOR signaling and autophagy in the pathophysiology and susceptibility to schizophrenia PubMed:30061532

Appears in Networks:

path(MESH:Schizophrenia) negativeCorrelation bp(GO:autophagy) View Subject | View Object

A few months later, another transcriptomic study reported a BA 22-specific down-regulation in several autophagy-related genes, thus strengthening the link between impaired autophagy and schizophrenia positive symptoms PubMed:30061532

Appears in Networks:

path(MESH:Schizophrenia) negativeCorrelation bp(GO:autophagy) View Subject | View Object

Later on, further analysis reported a disruption of the autophagy pathway also in the hippocampus of post-mortem schizophrenic patients PubMed:30061532

Appears in Networks:
Annotations
MeSH
Hippocampus

a(PUBCHEM:9832404) association bp(GO:autophagy) View Subject | View Object

Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381

Appears in Networks:

p(HGNC:ADNP) association bp(GO:autophagy) View Subject | View Object

Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381

Appears in Networks:

p(HGNC:ADNP) association bp(GO:autophagy) View Subject | View Object

ADNP expression in lymphocytes correlates with inflammation levels (36), disease state, and autophagy (13), as well as intelligence (40). PubMed:30106381

Appears in Networks:

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

Likewise, mechanistic target of rapamycin (Mtor), which has been linked to cellular regulation, protein translation, autophagy, and the actin cytoskeleton (43–45), was also found to be regulated by ADNP and NAP PubMed:30106381

Appears in Networks:

Out-Edges 99

bp(GO:autophagy) increases a(HBP:HBP00093) View Subject | View Object

a-syn accumulation has been linked to autophagic and lysosomal dysfunction, which may in turn lead to a-syn aggregation and production of more detrimental oligomers. PubMed:28803412

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

bp(GO:autophagy) negativeCorrelation g(HGNC:PSEN1, var("?")) View Subject | View Object

Fourth, genetic mutations and anomalies of presenilin 1, a dominant negative gene linked to AD, are associated with reduced lysosomal v-ATPase-mediated acidifica- tion 40,63 , a compromised ALN and deficient mitophagy 64 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

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

Mutant Htt is cleared by autophagy, but it compromises the ALN because of decreased cargo load- ing and impaired autophagosome formation and trans- port 55,56,68,92 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Huntington Disease

bp(GO:autophagy) association p(HGNC:NPEPPS) View Subject | View Object

PSA has been shown to be involved in the induction of autophagy and specifically the formation of autophagosomes, in a model of overexpressed mutant huntingtin (32). Thus, the in vivo effects of PSA on promoting tau clearance may relate to its ability to modulate the key clearance pathway for abnormal and aggregated proteins (to be described in more detail below). PubMed:24027553

Appears in Networks:
Annotations
MeSH
Huntington Disease
Text Location
Review

bp(GO:autophagy) association deg(p(HGNC:MAPT)) View Subject | View Object

PSA has been shown to be involved in the induction of autophagy and specifically the formation of autophagosomes, in a model of overexpressed mutant huntingtin (32). Thus, the in vivo effects of PSA on promoting tau clearance may relate to its ability to modulate the key clearance pathway for abnormal and aggregated proteins (to be described in more detail below). PubMed:24027553

Appears in Networks:
Annotations
MeSH
Huntington Disease
Text Location
Review

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

Tau proteins in a variety of forms are reported as degraded through the autophagy-lysosome system. PubMed:23528736

Appears in Networks:

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

Intracellular degradation of proteins occurs via the ubiquitin– proteasome pathway, the autophagy–lysosome pathway, and the endosome–lysosome pathway.56 PubMed:26195256

Appears in Networks:

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

It has been indicated that intracellular tau proteins are also degraded by autophagy and proteasomal pathways (Wang and Mandelkow 2012) PubMed:29626319

Appears in Networks:

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

Neuronal PAS domain protein 4 has been found to facilitate the autophagic clearance of endogenous total and phosphorylated tau in cortical neurons of rats PubMed:29626319

Appears in Networks:

bp(GO:autophagy) increases deg(p(HGNC:MAPT, pmod(Ph))) View Subject | View Object

Neuronal PAS domain protein 4 has been found to facilitate the autophagic clearance of endogenous total and phosphorylated tau in cortical neurons of rats PubMed:29626319

Appears in Networks:

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

Furthermore, autophagy can regulate both apoptosis and inflammasome assembly, and, depending on the conditions, can be either pro- or anti-apoptotic104 PubMed:23702978

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Apoptosis signaling subgraph

bp(GO:autophagy) regulates complex(GO:"inflammasome complex") View Subject | View Object

Furthermore, autophagy can regulate both apoptosis and inflammasome assembly, and, depending on the conditions, can be either pro- or anti-apoptotic104 PubMed:23702978

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Apoptosis signaling subgraph

bp(GO:autophagy) decreases act(complex(GO:"inflammasome complex")) View Subject | View Object

For inflammasome activation and IL-1β release, autophagy is a negative regulator: PubMed:23702978

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Interleukin signaling subgraph

bp(GO:autophagy) decreases sec(p(HGNC:IL1B)) View Subject | View Object

For inflammasome activation and IL-1β release, autophagy is a negative regulator: PubMed:23702978

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Interleukin signaling subgraph

bp(GO:autophagy) positiveCorrelation complex(p(HGNC:BAG3), p(HGNC:HSPB8)) View Subject | View Object

Overexpression of the HSPB8-BAG3 complex also stimulates autophagy and facilitates the clearance of mutated aggregation-prone proteins, the accumulation of which characterizes many neurodegenerative disorders such as Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis (Seidel et al., 2011). PubMed:22020111

Appears in Networks:

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

Robust AV accumulation in dystrophic neurites from biopsy tissues from patients with AD implicate a compromised state of autophagic flux PubMed:29758300

Appears in Networks:

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

Even early autophagic activation may become impaired due to progressively diminishing lysosomal clearance of substrates. PubMed:29758300

Appears in Networks:

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

Although the UPS is accountable for the degradation of up to 80–90% of proteins, misfolded proteins and aggregates are too large to be processed through the proteasome barrel and can impede UPS function by physical occlusion, leaving autophagic-lysosomal breakdown as the only effective pathway to clear these proteins [25,26] PubMed:29758300

Appears in Networks:

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

Although the UPS is accountable for the degradation of up to 80–90% of proteins, misfolded proteins and aggregates are too large to be processed through the proteasome barrel and can impede UPS function by physical occlusion, leaving autophagic-lysosomal breakdown as the only effective pathway to clear these proteins [25,26] PubMed:29758300

Appears in Networks:

bp(GO:autophagy) association p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Abnormal phosphorylation and truncation of tau are hallmarks of AD pathology and are targets of proteasome and autophagy pathways [27,44,45]. PubMed:29758300

Appears in Networks:

bp(GO:autophagy) increases deg(p(HGNC:MAPT, pmod(Ph))) View Subject | View Object

TFEB has been shown to effectively clear phosphorylated tau proteins through A-LS, resulting in ameliorated neuronal loss and neuroinflammation, as well as improved cognitive performance [89]. PubMed:29758300

Appears in Networks:

bp(GO:autophagy) association a(HBP:"Tau aggregates") View Subject | View Object

Tau aggregates can be targeted by two protein clearance pathways, the UPS and the A-LS, with the latter pathway encompassing microautophagy,CMA and macroautophagy. PubMed:29758300

Appears in Networks:

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

These experimental differences may be attributed to the intricate interplay between the UPS and autophagy, as α-synuclein is degraded by both proteolytic systems [62,63]. PubMed:29758300

Appears in Networks:

bp(GO:autophagy) decreases a(CHEBI:lipid) View Subject | View Object

Decreased autophagy in the diseased brain may contribute to aberrant lipid accumulation that occurs along with an increased incidence of the metabolic syndrome in aged humans [76] PubMed:29758300

Appears in Networks:

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

While autophagic-lysosomal degradation is more commonly associated with protein degradation, it serves to degrade all cellular material including carbohydrates and lipids. PubMed:29758300

Appears in Networks:

bp(GO:autophagy) negativeCorrelation a(CHEBI:lipid) View Subject | View Object

In addition to the direct modulation of protein generation, lipids can also influence the levels of proteins through autophagic clearance; for instance, increasing lipid contents has been shown to impair autophagy [72]. PubMed:29758300

Appears in Networks:

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

While autophagic-lysosomal degradation is more commonly associated with protein degradation, it serves to degrade all cellular material including carbohydrates and lipids. PubMed:29758300

Appears in Networks:

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

Modulation of mTOR can influence the levels of tau, with upregulation increasing tau phosphorylation and accumulation by reducing autophagic clearance [87], and conversely, pharmacological treatment with rapamycin reducing tau levels and rescuing motor deficits in the Tau P301S mice [53] PubMed:29758300

Appears in Networks:

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

A recent study has demonstrated that activation of AMPKα1 enhances tau phosphorylation, while inhibition reduces tau phosphorylation at Ser-262, an epitope that is increased in early stages of AD, which promotes the autophagic degradation of tau [87] PubMed:29758300

Appears in Networks:

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

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. PubMed:22908190

Appears in Networks:

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

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 PubMed:22908190

Appears in Networks:

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

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). PubMed:22908190

Appears in Networks:

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

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. PubMed:22908190

Appears in Networks:

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

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 PubMed:22908190

Appears in Networks:

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

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). PubMed:22908190

Appears in Networks:

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

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) PubMed:22908190

Appears in Networks:

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

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). PubMed:22908190

Appears in Networks:
Annotations
MeSH
Neurons

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

Indeed, many recent studies suggest the involvement of autophagy in the pathogenesis of AD PubMed:22908190

Appears in Networks:

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

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. PubMed:22908190

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

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

Similar autophagy pathology is observed when lysosomal proteolysis is inhibited (Ivy et al. 1984; Koike et al. 2005; Yang et al. 2008). PubMed:22908190

Appears in Networks:

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

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). PubMed:22908190

Appears in Networks:

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

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. PubMed:22908190

Appears in Networks:

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

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). PubMed:22908190

Appears in Networks:

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

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). PubMed:22908190

Appears in Networks:

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

Ab42-induced neurotoxicity is further enhanced by autophagy activation and is partially rescued by autophagy inhibition. PubMed:22908190

Appears in Networks:

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

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). PubMed:22908190

Appears in Networks:

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

The PN branch of degradation includes the ubiquitin- proteasome system (UPS) and machinery of autophagy (23, 196–200). PubMed:23746257

Appears in Networks:

bp(GO:autophagy) decreases a(MESH:"Protein Aggregates") View Subject | View Object

Aggregated proteins that cannot be un- folded for proteasomal degradation may be removed by autophagy and lysosomal/vacuolar degradation. PubMed:23746257

Appears in Networks:

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

Recent evidence suggests that the autophagic turnover of amyloid beta precursor protein (APP) may underlie the generation of toxic amyloid-β species [61]. PubMed:18930136

Appears in Networks:

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

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. PubMed:18930136

Appears in Networks:

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

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. PubMed:18930136

Appears in Networks:

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

“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. PubMed:18930136

Appears in Networks:

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

“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. PubMed:18930136

Appears in Networks:
Annotations
MeSH
Lysosomes

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

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]. PubMed:18930136

Appears in Networks:

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

“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. PubMed:18930136

Appears in Networks:

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

“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. PubMed:18930136

Appears in Networks:
Annotations
MeSH
Lysosomes

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

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]. PubMed:18930136

Appears in Networks:

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

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]. PubMed:18930136

Appears in Networks:

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

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]. PubMed:18930136

Appears in Networks:

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

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]. PubMed:18930136

Appears in Networks:

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

It has also been suggested that autophagy plays a role in the initiation or progression of some neurodegenerative diseases [20]. PubMed:18930136

Appears in Networks:

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

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]. PubMed:18930136

Appears in Networks:

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

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. PubMed:18930136

Appears in Networks:

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

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] PubMed:18930136

Appears in Networks:

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

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] PubMed:18930136

Appears in Networks:

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

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]. PubMed:18930136

Appears in Networks:

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

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]. PubMed:18930136

Appears in Networks:

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

It is becoming increasingly evident that the autophagy-lysosomal system is essential to neuronal homeostasis, and may in some settings be neuroprotective PubMed:18930136

Appears in Networks:

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

It is becoming increasingly evident that the autophagy-lysosomal system is essential to neuronal homeostasis, and may in some settings be neuroprotective PubMed:18930136

Appears in Networks:

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

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]. PubMed:18930136

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

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

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]. PubMed:18930136

Appears in Networks:

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

In addition to aggresome formation, impairment of the UPS in vitro has been found to induce autophagy [63,64]. PubMed:18930136

Appears in Networks:

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

Similar induction of autophagy is observed in response to genetic impairment of the proteasome in Drosophila [50]. PubMed:18930136

Appears in Networks:

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

Our previous work showed that inhibition of either the proteasome or autophagy in primary neurons induces pronounced neurotoxicity [23,24], making it impossible to address this issue in conventional neuron cultures. PubMed:30145931

Appears in Networks:

bp(GO:autophagy) decreases p(HGNC:MAPT) View Subject | View Object

In controls, the fraction of MAPT-containing dendrites on the neuritic side was low (~14%), but local treatment with inhibitors of either autophagy (wortmannin [Fig. 3B], bafilomycin A 1 [Fig. S3A]) or the proteasome (epoxomicin [Fig. 3C], lactacystin [Fig. S3B]) caused a pronounced 4-to 5-fold increase of MAPT-containing dendrites (to levels of ~50-76%) (Fig. 3D). PubMed:30145931

Appears in Networks:
Annotations
MeSH
Dendrites

bp(GO:autophagy) increases deg(p(HGNC:MAPT, pmod(Ph, Ser, 262))) View Subject | View Object

Thus, the dendritic and axonal MAPT are differentially phosphorylated. Based on this observation, we can conclude that the dendritic MAPT degraded by autophagy or proteasomal pathways is phosphorylated mainly at the 12E8 site. PubMed:30145931

Appears in Networks:
Annotations
MeSH
Dendrites

bp(GO:autophagy) increases deg(p(HGNC:MAPT, pmod(Ph, Ser, 356))) View Subject | View Object

Thus, the dendritic and axonal MAPT are differentially phosphorylated. Based on this observation, we can conclude that the dendritic MAPT degraded by autophagy or proteasomal pathways is phosphorylated mainly at the 12E8 site. PubMed:30145931

Appears in Networks:
Annotations
MeSH
Dendrites

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

The two major pathways for protein degradation in cells are through the ubiquitin-proteasome system and the autophagy-lysosome system [10, 11], both of which have been implicated in tau degradation in AD [12]. PubMed:25374103

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

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

Remarkably, further investigation on the autophagy pathway revealed that all these misfolded proteins are autophagy substrates depending on mTOR activity PubMed:30061532

Appears in Networks:

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

Therefore, a common pathogenesis underlying all these NDDs disorders has been linked to autophagy inhibition due to mTOR hyperactivation PubMed:30061532

Appears in Networks:

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

Therefore, a common pathogenesis underlying all these NDDs disorders has been linked to autophagy inhibition due to mTOR hyperactivation PubMed:30061532

Appears in Networks:

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

The relevance of autophagy for sustaining these mTOR-induced effects is confirmed by drugs inducing autophagy independently of mTOR activation PubMed:30061532

Appears in Networks:

bp(GO:autophagy) decreases act(a(CHEBI:methamphetamine)) View Subject | View Object

In fact, mTOR-induced autophagy inhibition exacerbates the ultrastructural effects of METH [126,134–136], while rapamycin administration reverts both behavioral and morphological alterations induced by METH [137]. PubMed:30061532

Appears in Networks:

bp(GO:autophagy) decreases act(a(CHEBI:methamphetamine)) View Subject | View Object

This confirms our previous studies showing that both genetic and pharmacological autophagy inhibition worsen the effects of METH administration PubMed:30061532

Appears in Networks:

bp(GO:autophagy) decreases sec(a(CHEBI:dopamine)) View Subject | View Object

Noteworthy, genetic ablation of autophagy was shown to produce an extremely powerful DA release upon electrical stimuli, suggesting that autophagy is key to restrain DA release both upon basal neural activity and mostly after rapamycin-induced autophagy PubMed:30061532

Appears in Networks:

bp(GO:autophagy) decreases sec(a(CHEBI:dopamine)) View Subject | View Object

These findings strongly suggest that an autophagy dysfunction acts both at pre- and post-synaptic level to alter DA neurotransmission during both METH administration and schizophrenia (Figure 2) PubMed:30061532

Appears in Networks:
Annotations
MeSH
Schizophrenia

bp(GO:autophagy) association bp(GO:"dopamine secretion, neurotransmission") View Subject | View Object

These findings strongly suggest that an autophagy dysfunction acts both at pre- and post-synaptic level to alter DA neurotransmission during both METH administration and schizophrenia (Figure 2) PubMed:30061532

Appears in Networks:
Annotations
MeSH
Schizophrenia

bp(GO:autophagy) negativeCorrelation path(MESH:Schizophrenia) View Subject | View Object

Remarkably, the identification of rare genetic variants of ULK1 in a cohort of schizophrenic patients by means of exome sequence analysis strengthens the idea of a key role of both disrupted mTOR signaling and autophagy in the pathophysiology and susceptibility to schizophrenia PubMed:30061532

Appears in Networks:

bp(GO:autophagy) negativeCorrelation path(MESH:Schizophrenia) View Subject | View Object

A few months later, another transcriptomic study reported a BA 22-specific down-regulation in several autophagy-related genes, thus strengthening the link between impaired autophagy and schizophrenia positive symptoms PubMed:30061532

Appears in Networks:

bp(GO:autophagy) negativeCorrelation path(MESH:Schizophrenia) View Subject | View Object

Later on, further analysis reported a disruption of the autophagy pathway also in the hippocampus of post-mortem schizophrenic patients PubMed:30061532

Appears in Networks:
Annotations
MeSH
Hippocampus

bp(GO:autophagy) association p(HGNC:BECN1) View Subject | View Object

In particular, at BA 22, the vast majority of abnormally expressed genes referred to key autophagy genes (i.e., BECN1, ULK2, ATG3), which were significantly down-regulated compared with controls PubMed:30061532

Appears in Networks:

bp(GO:autophagy) association p(HGNC:ULK2) View Subject | View Object

In particular, at BA 22, the vast majority of abnormally expressed genes referred to key autophagy genes (i.e., BECN1, ULK2, ATG3), which were significantly down-regulated compared with controls PubMed:30061532

Appears in Networks:

bp(GO:autophagy) association p(HGNC:ATG3) View Subject | View Object

In particular, at BA 22, the vast majority of abnormally expressed genes referred to key autophagy genes (i.e., BECN1, ULK2, ATG3), which were significantly down-regulated compared with controls PubMed:30061532

Appears in Networks:

bp(GO:autophagy) negativeCorrelation path(MESH:Hallucinations) View Subject | View Object

A few months later, another transcriptomic study reported a BA 22-specific down-regulation in several autophagy-related genes, thus strengthening the link between impaired autophagy and schizophrenia positive symptoms PubMed:30061532

Appears in Networks:

bp(GO:autophagy) association p(HGNC:ADNP) View Subject | View Object

Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381

Appears in Networks:

bp(GO:autophagy) association p(HGNC:ADNP) View Subject | View Object

ADNP expression in lymphocytes correlates with inflammation levels (36), disease state, and autophagy (13), as well as intelligence (40). PubMed:30106381

Appears in Networks:

bp(GO:autophagy) association a(PUBCHEM:9832404) View Subject | View Object

Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381

Appears in Networks:

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

Likewise, mechanistic target of rapamycin (Mtor), which has been linked to cellular regulation, protein translation, autophagy, and the actin cytoskeleton (43–45), was also found to be regulated by ADNP and NAP PubMed:30106381

Appears in Networks:

bp(GO:autophagy) increases deg(p(HGNC:MAPT, pmod(Ph, Ser, 262), pmod(Ph, Ser, 356))) View Subject | View Object

Thus, the dendritic and axonal MAPT are differentially phosphorylated. Based on this observation, we can conclude that the dendritic MAPT degraded by autophagy or proteasomal pathways is phosphorylated mainly at the 12E8 site. PubMed:30145931

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Dendrites

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.