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PubMed: 25784053

Title
The biology of proteostasis in aging and disease.
Journal
Annual review of biochemistry
Volume
84
Issue
None
Pages
435-64
Date
2015-01-01
Authors
Labbadia J | Morimoto RI

Evidence c065d7bb8e
JSON

Experiments examining the effects of Aβ on proteasomal activity in vitro revealed an inhibitory effect on the chymotrypsin-like properties of the 20S core (73), consistent with observations of impaired proteasome function in AD patient brains (74).

a(CHEBI:"amyloid-beta") decreases act(p(FPLX:Proteasome)) View Subject | View Object

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act(p(FPLX:Proteasome)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(FPLX:Proteasome)) View Subject | View Object

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Annotations
MeSH
Brain

Evidence 6a76e829c1
JSON

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).

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

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Cell Ontology (CL)
motor neuron

a(CHEBI:chloroquine) increases a(CHEBI:"N-retinylidene-N-retinylethanolamine") View Subject | View Object

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Annotations
Cell Ontology (CL)
motor neuron

a(CHEBI:chloroquine) increases p(HGNC:MAP1LC3A) View Subject | View Object

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Cell Ontology (CL)
motor neuron

a(CHEBI:chloroquine) increases p(HGNC:SQSTM1) View Subject | View Object

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

p(HGNC:SOD1, var("p.Gly576Arg")) decreases a(CHEBI:"N-retinylidene-N-retinylethanolamine") View Subject | View Object

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

p(HGNC:SOD1, var("p.Gly576Arg")) decreases p(HGNC:MAP1LC3A) View Subject | View Object

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Annotations
Cell Ontology (CL)
motor neuron

p(HGNC:SOD1, var("p.Gly576Arg")) decreases p(HGNC:SQSTM1) View Subject | View Object

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

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

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

Evidence ad613012c4
JSON

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).

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

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Cell Ontology (CL)
motor neuron

a(CHEBI:fluphenazine) decreases p(HGNC:TARDBP) View Subject | View Object

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

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

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

a(CHEBI:methotrimeprazine) decreases p(HGNC:TARDBP) View Subject | View Object

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

a(PUBCHEM:10521421) decreases act(p(FPLX:AKT)) View Subject | View Object

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

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

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

Evidence b0e20ed973
JSON

One strategy is to directly activate HSF1, thereby increasing the expression of multiple molecular chaperones simultaneously. This approach has been traditionally achieved by inhibition of HSP90 with compounds that bind the N-terminal ATP-binding pocket, such as radicicol, geldanamycin, or 17-AAG (64, 132–134).

a(CHEBI:geldanamycin) decreases act(p(FPLX:HSP90)) View Subject | View Object

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Cell Ontology (CL)
motor neuron

a(CHEBI:radicicol) decreases act(p(FPLX:HSP90)) View Subject | View Object

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Cell Ontology (CL)
motor neuron

a(CHEBI:tanespimycin) decreases act(p(FPLX:HSP90)) View Subject | View Object

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Annotations
Cell Ontology (CL)
motor neuron

act(p(FPLX:HSP90)) decreases act(p(HGNC:HSF1)) View Subject | View Object

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

Evidence b5c8657199
JSON

Treatment of cell, Drosophila, and mouse models of HD, SCA3/MJD, AD, PD, and ALS with the mTOR inhibitor rapamycin (or a derivative) reduces aggregation and suppresses disease (140– 143).

a(CHEBI:sirolimus) decreases act(p(FPLX:mTORC1)) View Subject | View Object

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Annotations
Cell Ontology (CL)
motor neuron

a(CHEBI:sirolimus) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

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Annotations
Cell Ontology (CL)
motor neuron

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

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Annotations
Cell Ontology (CL)
motor neuron

a(CHEBI:sirolimus) decreases path(MESH:"Machado-Joseph Disease") View Subject | View Object

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Annotations
Cell Ontology (CL)
motor neuron

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

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

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

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

a(CHEBI:sirolimus) decreases path(MESH:"Amyotrophic Lateral Sclerosis") View Subject | View Object

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

Evidence f27c39fb08
JSON

TRiC is essential for proper posttranslational folding of the cytoskeletal components actin and tubulin and is therefore essential for cell structure, division, and cargo delivery (11).

a(MESH:"Cellular Structures") association p(FPLX:"CCT_complex") View Subject | View Object

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bp(GO:"cell division") association p(FPLX:"CCT_complex") View Subject | View Object

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bp(GO:"intracellular transport") association p(FPLX:"CCT_complex") View Subject | View Object

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p(FPLX:"CCT_complex") association a(MESH:"Cellular Structures") View Subject | View Object

Appears in Networks:

p(FPLX:"CCT_complex") association bp(GO:"cell division") View Subject | View Object

Appears in Networks:

p(FPLX:"CCT_complex") association bp(GO:"intracellular transport") View Subject | View Object

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Evidence 1bca54d57e
JSON

As discussed above, one approach is to employ specialized molecular chaperone machines to release misfolded proteins from aggregates and direct them to the proteasome for degradation (19).

a(MESH:"Molecular Chaperones") decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

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p(FPLX:Proteasome) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

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Evidence 40d96dcf19
JSON

. Proteins can be degraded either individually or en masse by proteasomes (20) or lysosomes (21), respectively.

a(MESH:Lysosomes) increases bp(MESH:Proteolysis) View Subject | View Object

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p(FPLX:Proteasome) increases bp(MESH:Proteolysis) View Subject | View Object

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Evidence 9b39d34b8e
JSON

Alternatively, bulkier substrates, such as large inclusions, can be directed to the lysosome, a membrane-bound organelle containing a host of nonspecific proteases that can degrade a wide range of substrates (21).

a(MESH:Lysosomes) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

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Evidence fae8e2901a
JSON

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

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

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

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

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

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

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

Evidence 5668c7034e
JSON

Treatment of PC12 cells stably expressing mutant α-synuclein (A53T) with SMER-10, -18, or-28 significantly reduced levels of mutant α-synuclein, an effect that was enhanced by cotreatment with rapamycin (146).

a(PUBCHEM:1560402) decreases p(HGNC:SNCA, var("p.Ala53Thr")) View Subject | View Object

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Annotations
Cell Ontology (CL)
motor neuron

a(PUBCHEM:799645) decreases p(HGNC:SNCA, var("p.Ala53Thr")) View Subject | View Object

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Annotations
Cell Ontology (CL)
motor neuron

a(PUBCHEM:877863) decreases p(HGNC:SNCA, var("p.Ala53Thr")) View Subject | View Object

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

composite(a(CHEBI:sirolimus), a(PUBCHEM:1560402)) decreases p(HGNC:SNCA, var("p.Ala53Thr")) View Subject | View Object

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

composite(a(CHEBI:sirolimus), a(PUBCHEM:799645)) decreases p(HGNC:SNCA, var("p.Ala53Thr")) View Subject | View Object

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

composite(a(CHEBI:sirolimus), a(PUBCHEM:877863)) decreases p(HGNC:SNCA, var("p.Ala53Thr")) View Subject | View Object

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

Evidence 02ccef1690
JSON

In addition, SMER-10, -18, and -28 were effective at suppressing mHTT aggregation and toxicity in COS-7 cells and flies (146).

a(PUBCHEM:1560402) decreases a(HBP:"huntingtin aggregates") View Subject | View Object

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Annotations
Cell Ontology (CL)
motor neuron

a(PUBCHEM:799645) decreases a(HBP:"huntingtin aggregates") View Subject | View Object

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

a(PUBCHEM:877863) decreases a(HBP:"huntingtin aggregates") View Subject | View Object

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

Evidence 27a7413a7e
JSON

High-throughput screens in yeast and HeLa cells identified HSF1A and F1, respectively, as two small molecules that activate HSF1 independently of HSP90 inhibition (136, 137).

a(PUBCHEM:377503130) increases act(p(HGNC:HSF1)) View Subject | View Object

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

Evidence 0d3d4da846
JSON

HSF1A suppresses toxicity in cell and tissue culture models of HD and SCA-3/MJD and appears to activate HSF1 by impairing the activity of TRiC, a recently discovered negative regulator of HSF1.

a(PUBCHEM:377503130) decreases act(p(FPLX:"CCT_complex")) View Subject | View Object

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

p(FPLX:"CCT_complex") decreases act(p(HGNC:HSF1)) View Subject | View Object

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

Evidence 44df4d5af9
JSON

Treatment with IU1 reduced the levels of Tau, TDP-43, and ataxin-3 in MEFs in a USP14-dependent manner and independently of changes in proteasome levels or composition (147).

a(PUBCHEM:675434) decreases p(HGNC:MAPT) View Subject | View Object

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Annotations
Experimental Factor Ontology (EFO)
MEF cell line
Cell Ontology (CL)
motor neuron

a(PUBCHEM:675434) decreases p(HGNC:TARDBP) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
MEF cell line
Cell Ontology (CL)
motor neuron

a(PUBCHEM:675434) decreases p(HGNC:ATXN3) View Subject | View Object

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Annotations
Experimental Factor Ontology (EFO)
MEF cell line
Cell Ontology (CL)
motor neuron

a(PUBCHEM:675434) decreases act(p(HGNC:USP14)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
MEF cell line
Cell Ontology (CL)
motor neuron

a(PUBCHEM:675434) causesNoChange p(FPLX:Proteasome) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
MEF cell line
Cell Ontology (CL)
motor neuron

Evidence e4a67b2650
JSON

ATP hydrolysisis essential for the chaperone activity of HSP70 and HSP90, causing conformational changes that result in substrate binding (11).

bp(GO:"ATP metabolic process") increases act(p(FPLX:HSPA)) View Subject | View Object

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bp(GO:"ATP metabolic process") increases act(p(FPLX:HSP90)) View Subject | View Object

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Evidence 653c1da1a8
JSON

Proteome fidelity is maintained by the protein homeostasis (proteostasis) network (PN), a multi-compartmental system that coordinatesprotein synthesis, folding, disaggregation, and degradation (1).

bp(GO:"protein folding") association bp(HBP:Proteostasis) View Subject | View Object

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bp(HBP:Proteostasis) association bp(MESH:"Protein Biosynthesis") View Subject | View Object

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bp(HBP:Proteostasis) association bp(GO:"protein folding") View Subject | View Object

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bp(HBP:Proteostasis) association path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

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bp(HBP:Proteostasis) association bp(MESH:Proteolysis) View Subject | View Object

Appears in Networks:

bp(MESH:"Protein Biosynthesis") association bp(HBP:Proteostasis) View Subject | View Object

Appears in Networks:

bp(MESH:Proteolysis) association bp(HBP:Proteostasis) View Subject | View Object

Appears in Networks:

path(MESH:"Protein Aggregation, Pathological") association bp(HBP:Proteostasis) View Subject | View Object

Appears in Networks:

Evidence 8f4a01b066
JSON

Upon increased levels of nonnative proteins, HSF1 is released from its repressive complex, acquires DNA-binding activity through homotrimerization, and rapidly translocates to the nucleus to induce expression of genes encoding molecular chaperones (7, 35).

bp(GO:"response to misfolded protein") increases act(p(HGNC:HSF1)) View Subject | View Object

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act(p(HGNC:HSF1)) increases tloc(p(HGNC:HSF1), fromLoc(MESH:Cytosol), toLoc(MESH:"Cell Nucleus")) View Subject | View Object

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act(p(HGNC:HSF1), ma(tscript)) increases a(MESH:"Molecular Chaperones") View Subject | View Object

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Evidence fd11c1a732
JSON

IRE1 is a transmembrane protein with kinase and endoribonuclease (RNase) activity that senses misfolding in the ER directly, leading to autophosphorylation, oligomerization, and acquisition of RNase activity (8).

bp(GO:"response to misfolded protein") increases act(p(HGNC:ERN1), ma(kin)) View Subject | View Object

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Annotations
MeSH
Endoplasmic Reticulum

act(p(HGNC:ERN1), ma(kin)) increases p(HGNC:ERN1, pmod(Ph)) View Subject | View Object

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Annotations
MeSH
Endoplasmic Reticulum

p(HGNC:ERN1, pmod(Ph)) increases act(p(HGNC:ERN1), ma(GO:"ribonuclease activity")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endoplasmic Reticulum

Evidence 4c2a692235
JSON

Consistent with a role of autophagy in disease, AD patient tissues exhibit impaired initiation of macroautophagy and an excess of autophagic vacuoles in dystrophic neurites, possibly due to impaired targeting of the vacuolar ATPase to the lysosome (86, 87).

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

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

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Evidence 085a4e0b3f
JSON

As such, it is feasible that any reduction in the protein degradation capacity of a cell could contribute to proteostasis collapse and promote aging.

bp(HBP:Proteostasis) decreases bp(MESH:Aging) View Subject | View Object

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

Evidence 81b86ae032
JSON

In parallel, ER stress promotes the relocation of ATF6 from the ER membrane to the Golgi apparatus, where it is cleaved by SP1 and SP2 proteases.

bp(MESH:"Endoplasmic Reticulum Stress") increases tloc(p(HGNC:ATF6), fromLoc(MESH:"Endoplasmic Reticulum"), toLoc(MESH:"Golgi Apparatus")) View Subject | View Object

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p(HGNC:PRSS1) decreases p(HGNC:ATF6) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Golgi Apparatus

p(HGNC:PRSS1) increases p(HBP:"N-terminal fragment of ATF6") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Golgi Apparatus

p(HGNC:PRSS2) decreases p(HGNC:ATF6) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Golgi Apparatus

p(HGNC:PRSS2) increases p(HBP:"N-terminal fragment of ATF6") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Golgi Apparatus

Evidence 9276f4bb33
JSON

Finally, a third ER transmembrane protein, PERK, promotes translation of the TF ATF4 by phosphorylating the translation initiation factor eIF2α in response to ER stress.

bp(MESH:"Endoplasmic Reticulum Stress") increases act(p(HGNC:EIF2AK3), ma(kin)) View Subject | View Object

Appears in Networks:

act(p(HGNC:EIF2AK3), ma(kin)) increases p(HGNC:EIF2S1, pmod(Ph)) View Subject | View Object

Appears in Networks:

act(p(HGNC:EIF2S1), ma(tscript)) increases p(HGNC:ATF4) View Subject | View Object

Appears in Networks:

p(HGNC:EIF2S1, pmod(Ph)) increases act(p(HGNC:EIF2S1), ma(tscript)) View Subject | View Object

Appears in Networks:

Evidence 123f884a11
JSON

HSP60 is essential for maturation and maintenance of the mitochondrial proteome and is therefore intimately linked to energy production.

bp(MESH:"Energy Metabolism") association p(HGNC:HSPD1) View Subject | View Object

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Annotations
MeSH
Mitochondria

p(HGNC:HSPD1) increases bp(HBP:Proteostasis) View Subject | View Object

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Annotations
MeSH
Mitochondria

p(HGNC:HSPD1) association bp(MESH:"Energy Metabolism") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Mitochondria

Evidence 0f37af5ab0
JSON

Furthermore, the activity of the PN can be altered permanently or transiently by development and aging, alterations in physiology, or exposure to environmental stress (1).

bp(MESH:"Growth and Development") regulates bp(HBP:Proteostasis) View Subject | View Object

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bp(MESH:"Stress, Physiological") regulates bp(HBP:Proteostasis) View Subject | View Object

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bp(MESH:Aging) regulates bp(HBP:Proteostasis) View Subject | View Object

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Evidence 96d573fe45
JSON

Additionally, an investigation of chaperone and cochaperone gene expression in young (36±4 years of age) and aged (73 ±4 years of age) human brain tissue revealed that of 332 genes examined, 101 are significantly repressed with age, including HSP70, HSP40, HSP90, and TRiC genes (113). Furthermore, 62 chaperone genes, including several small HSPs, were found to be significantly induced, likely as a result of the cellular response to accumulating protein damage with age (113).

bp(MESH:Aging) decreases p(FPLX:HSPA) View Subject | View Object

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

bp(MESH:Aging) decreases p(FPLX:HSP90) View Subject | View Object

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

bp(MESH:Aging) decreases p(HGNCGENEFAMILY:"DNAJ (HSP40) heat shock proteins") View Subject | View Object

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

bp(MESH:Aging) increases p(FPLX:HSPB) View Subject | View Object

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

Evidence a73a405d67
JSON

Once stress has been relieved, HSF1 activity is repressed through acetylation and binding to molecular chaperones (34, 36, 37).

complex(a(MESH:"Molecular Chaperones"), p(HGNC:HSF1)) decreases act(p(HGNC:HSF1)) View Subject | View Object

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p(HGNC:HSF1, pmod(Ac)) decreases act(p(HGNC:HSF1)) View Subject | View Object

Appears in Networks:

Evidence 913c4f8a44
JSON

Constitutive activation of HSF1 is detrimental to cells and increased expression, and activity of HSF1 has been linked to multiple forms of cancer, highlighting the need for appropriate and balanced activation of stress response pathways as and when required throughout life (122).

act(p(HGNC:HSF1)) association path(MESH:Neoplasms) View Subject | View Object

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

path(MESH:Neoplasms) association act(p(HGNC:HSF1)) View Subject | View Object

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

Evidence 21851b5445
JSON

Perhaps the most significant example of this process is that the HSP110 molecular chaperone, long considered simply a NEF, can catalyze protein disaggregation as part of a complex containing HSP70 and DNAJ/HSP40 (18).

complex(p(FPLX:HSPA), p(HGNC:DNAJB1), p(HGNC:HSPH1)) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Appears in Networks:

Evidence a7e7972c0d
JSON

As such, HSP70 and HSP90 are central to the process of triaging proteins for refolding or elimination.

p(FPLX:HSPA) regulates bp(GO:"protein folding") View Subject | View Object

Appears in Networks:

p(FPLX:HSPA) regulates bp(MESH:Proteolysis) View Subject | View Object

Appears in Networks:

p(FPLX:HSP90) regulates bp(GO:"protein folding") View Subject | View Object

Appears in Networks:

p(FPLX:HSP90) regulates bp(MESH:Proteolysis) View Subject | View Object

Appears in Networks:

Evidence 932a4379fe
JSON

Furthermore, increased levels of HSP70 were found in the cerebellar cortex of human HD brain samples but not in tissue from unaffected individuals or from brains of PD patients (57).

p(FPLX:HSPA) positiveCorrelation path(MESH:"Huntington Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:"Huntington Disease") positiveCorrelation p(FPLX:HSPA) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence 40e75dd19c
JSON

Studies of chaperone levels in tissue culture and mouse models of polyQ disease showed that the levels of HSP70 (HSPA1A/B) and DNAJ/HSP40 (DNAJB1), as well as some cochaperones, decline with protein aggregation (64, 65).

p(HGNC:DNAJB1) negativeCorrelation path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Appears in Networks:

p(HGNC:HSPA1A) negativeCorrelation path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Appears in Networks:

p(HGNC:HSPA1B) negativeCorrelation path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Appears in Networks:

path(MESH:"Protein Aggregation, Pathological") negativeCorrelation p(HGNC:HSPA1A) View Subject | View Object

Appears in Networks:

path(MESH:"Protein Aggregation, Pathological") negativeCorrelation p(HGNC:HSPA1B) View Subject | View Object

Appears in Networks:

path(MESH:"Protein Aggregation, Pathological") negativeCorrelation p(HGNC:DNAJB1) View Subject | View Object

Appears in Networks:

Evidence e4a7a3e81c
JSON

The cytosolic N-terminal fragment of ATF6 that is generated translocates to the nucleus, binds DNA, and drives expression of a complementary set of UPR genes (8).

tloc(p(HBP:"N-terminal fragment of ATF6"), fromLoc(MESH:Cytosol), toLoc(MESH:"Cell Nucleus")) increases act(p(HBP:"N-terminal fragment of ATF6"), ma(tscript)) View Subject | View Object

Appears in Networks:

act(p(HBP:"N-terminal fragment of ATF6"), ma(tscript)) increases bp(GO:"response to misfolded protein") View Subject | View Object

Appears in Networks:

Evidence 071bed0020
JSON

Under these conditions, ATF4 mRNA is preferentially translated, leading to selective expression of the proapoptotic TF CHOP, which elicits apoptosis if ER stress is not resolved, presumably to ensure that irreversibly damaged cells are removed from the population.

p(HGNC:ATF4) increases p(HGNC:DDIT3) View Subject | View Object

Appears in Networks:

p(HGNC:DDIT3) increases bp(GO:"apoptotic process") View Subject | View Object

Appears in Networks:

Evidence 12df938d17
JSON

Disruption of the ATF6 arm of the UPR(ER) is reported to occur in mouse models of HD and a VAPB cell model of ALS, suggesting that differential changes in UPR arms may be a feature of disease progression (102, 103).

p(HGNC:ATF6) negativeCorrelation path(MESH:"Amyotrophic Lateral Sclerosis") View Subject | View Object

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

p(HGNC:ATF6) negativeCorrelation path(MESH:"Huntington Disease") View Subject | View Object

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

path(MESH:"Amyotrophic Lateral Sclerosis") negativeCorrelation p(HGNC:ATF6) View Subject | View Object

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

path(MESH:"Huntington Disease") negativeCorrelation p(HGNC:ATF6) View Subject | View Object

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

Evidence 06342b7230
JSON

Cerebellar granular neurons were found to express high levels of HSP70 in response to mHTT expression but not mAtaxin-1.

p(HGNC:ATXN1, var("?")) causesNoChange p(FPLX:HSPA) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
cerebellar granule cell

p(HGNC:HTT, var("?")) increases p(FPLX:HSPA) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
cerebellar granule cell

Evidence e18f0b2d62
JSON

This process allows active IRE1 to cleave XBP1 messenger RNA (mRNA), thereby generating a spliced transcript (XBP1s) that encodes a stable form of XBP1 that binds DNA and induces transcription of UPR target genes (8).

act(p(HGNC:ERN1), ma(GO:"ribonuclease activity")) increases p(HGNC:XBP1) View Subject | View Object

Appears in Networks:

act(p(HGNC:XBP1), ma(tscript)) increases bp(GO:"response to misfolded protein") View Subject | View Object

Appears in Networks:

Evidence 535168135c
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In contrast, α-synuclein overexpression impairs autophagy in mammalian cells and mice through reduced expression of RAB1A, thereby inhibiting autophagosome formation (88).

p(HGNC:RAB1A) increases bp(GO:"autophagosome assembly") View Subject | View Object

Appears in Networks:

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

Appears in Networks:

p(HGNC:SNCA) decreases p(HGNC:RAB1A) View Subject | View Object

Appears in Networks:

Evidence 5ed259cf17
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The DUB USP14 suppresses turnover of Tau and TDP-43 in mouse embryonic fibroblasts (MEFs) by impairing the protea-some;

p(HGNC:USP14) decreases deg(p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
MEF cell line
Cell Ontology (CL)
motor neuron

p(HGNC:USP14) decreases deg(p(HGNC:TARDBP)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
MEF cell line
Cell Ontology (CL)
motor neuron

p(HGNC:USP14) decreases act(p(FPLX:Proteasome)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
MEF cell line
Cell Ontology (CL)
motor neuron

Evidence f73af5c4db
JSON

Mice deficient for the autophagy-related genes Atg5 and Atg7 exhibit severe neurodegeneration (84, 85), and the expression of disease- associated proteins is reported to exert differential inhibitory effects on autophagic pathways.

p(MGI:Atg5) decreases bp(HP:Neurodegeneration) View Subject | View Object

Appears in Networks:

p(MGI:Atg7) decreases bp(HP:Neurodegeneration) View Subject | View Object

Appears in Networks:

Evidence 36f348e60d
JSON

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

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

Appears in Networks:

Evidence 264857a135
JSON

Protein aggregation is recognized as a hallmark of neurodegenerative disease by the consistent appearance of detergent-insoluble inclusions and aggregates in the nucleus and cytoplasm of neurons.

path(MESH:"Neurodegenerative Diseases") association path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Nucleus
MeSH
Cytoplasm
MeSH
Neurons

path(MESH:"Protein Aggregation, Pathological") association path(MESH:"Neurodegenerative Diseases") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Nucleus
MeSH
Cytoplasm
MeSH
Neurons

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.