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PubMed: 27491084

Title
Model systems of protein-misfolding diseases reveal chaperone modifiers of proteotoxicity.
Journal
Disease models & mechanisms
Volume
9
Issue
None
Pages
823-38
Date
2016-08-01
Authors
Brehme M | Voisine C

Evidence 803ac26b46
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The importance of sHSPs in disease was originally noted from the observations that HSPB1 and CRYAB were overexpressed in AD brains (Shinohara et al., 1993; Renkawek et al., 1994a,b) and HSPB1, CRYAB, HSPB6 and HSPB8 were associated with AD plaques (Shao et al., 2012).

a(HBP:"amyloid-beta aggregates") association p(HGNC:HSPB1) View Subject | View Object

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a(HBP:"amyloid-beta aggregates") association p(HGNC:CRYAB) View Subject | View Object

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a(HBP:"amyloid-beta aggregates") association p(HGNC:HSPB6) View Subject | View Object

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a(HBP:"amyloid-beta aggregates") association p(HGNC:HSPB8) View Subject | View Object

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p(HGNC:CRYAB) association a(HBP:"amyloid-beta aggregates") View Subject | View Object

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p(HGNC:HSPB1) association a(HBP:"amyloid-beta aggregates") View Subject | View Object

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p(HGNC:HSPB6) association a(HBP:"amyloid-beta aggregates") View Subject | View Object

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p(HGNC:HSPB8) association a(HBP:"amyloid-beta aggregates") View Subject | View Object

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path(MESH:"Alzheimer Disease") increases p(HGNC:HSPB1) View Subject | View Object

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Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") increases p(HGNC:CRYAB) View Subject | View Object

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Annotations
MeSH
Brain

Evidence 52edaaf083
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Genetic approaches using these disease models demonstrate that the chaperome plays a crucial role in protecting cells from proteotoxicity.

a(MESH:"Molecular Chaperones") decreases path(HBP:proteotoxicity) View Subject | View Object

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Evidence ad8c43f332
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Compounds such as the allosteric inhibitor of ATP-binding for the inducible HSP70 isoform HSPA1A/HSPA1B, called HS-72, will likely lead to beneficial consequences (Howe et al., 2014).

a(PUBCHEM:40009526) decreases complex(a(CHEBI:ATP), p(HGNC:HSPA1A)) View Subject | View Object

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a(PUBCHEM:40009526) decreases complex(a(CHEBI:ATP), p(HGNC:HSPA1B)) View Subject | View Object

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Evidence 1a2584be89
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The HSP70 and HSP40 family members exhibit significantly altered expression dynamics during aging in the human brain, both being consistently repressed with age (Brehme et al., 2014).

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

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bp(GO:aging) decreases p(FPLX:HSPA) View Subject | View Object

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Evidence 55c578542a
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Furthermore, sHSPs were found to be consistently upregulated in the aging human brain and in the context of neurodegenerative diseases (Brehme et al., 2014).

bp(GO:aging) increases p(FPLX:HSPB) View Subject | View Object

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Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") increases p(FPLX:HSPB) View Subject | View Object

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Annotations
MeSH
Brain

Evidence c7298d4d26
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Many studies based on model systems support a role for candidates from each of the major chaperome families; HSP100, HSP90, HSP70, HSP60, HSP40, sHSPs, and TPR-domain-containing proteins in proteostasis.

bp(HBP:Proteostasis) association p(HGNCGENEFAMILY:"DNAJ (HSP40) heat shock proteins") View Subject | View Object

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

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bp(HBP:Proteostasis) association p(FPLX:HSPA) View Subject | View Object

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bp(HBP:Proteostasis) association p(HGNC:TPR) View Subject | View Object

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bp(HBP:Proteostasis) association p(FPLX:HSPB) View Subject | View Object

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bp(HBP:Proteostasis) association p(FPLX:HSP90) View Subject | View Object

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bp(HBP:Proteostasis) association p(HGNCGENEFAMILY:"AAA ATPases") View Subject | View Object

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p(FPLX:HSP90) association bp(HBP:Proteostasis) View Subject | View Object

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p(FPLX:HSPA) association bp(HBP:Proteostasis) View Subject | View Object

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p(FPLX:HSPB) association bp(HBP:Proteostasis) View Subject | View Object

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

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p(HGNC:TPR) association bp(HBP:Proteostasis) View Subject | View Object

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p(HGNCGENEFAMILY:"AAA ATPases") association bp(HBP:Proteostasis) View Subject | View Object

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p(HGNCGENEFAMILY:"DNAJ (HSP40) heat shock proteins") association bp(HBP:Proteostasis) View Subject | View Object

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Evidence 2337fbbcbc
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Our summary (Table 1) points towards specific sHSPs that play a prominent role in misfolding diseases, as judged by frequency of observations, including CRYAB, HSPB1, HSPB3 and HSPB8 (each 7×), HSPB6 (6×), and CRYAA (5×) (Fig. 1).

bp(HBP:misfolding) association p(FPLX:HSPB) View Subject | View Object

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p(FPLX:HSPB) association bp(HBP:misfolding) View Subject | View Object

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Evidence 6e859aab60
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The HSP40, HSP60 and HSP70 families were amongst the most repressed chaperones, with HSP70s being the most repressed group overall. However, in contrast with the broad spectrum of repressed chaperone families, sHSPs and the TPR co-chaperone proteins were the only families that were significantly induced.

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

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bp(MESH:Aging) decreases p(HGNC:HSPD1) View Subject | View Object

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

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bp(MESH:Aging) increases p(HGNC:TPR) View Subject | View Object

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

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Evidence b4394f828e
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In a yeast model expressing the N-terminal fragment of a polyQ-containing huntingtin protein, overexpression of the yeast HSP70 (SSA1) reduced aggregate formation, whereas the dominant-negative version of the fly homolog to HSPA1L, Hsc4-K71S, enhanced neurodegeneration (Warrick et al., 1999;)

p(FPLX:HSPA) decreases p(HBP:"huntingtin aggregates") View Subject | View Object

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p(HGNC:HSPA1L) decreases path(HP:Neurodegeneration) View Subject | View Object

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Evidence fbbb245cfe
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These studies revealed that an increase in levels of HSP70 reduced aggregation of disease-associated proteins, thus playing a neuroprotective role.

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

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Evidence e967bd058c
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HSP70s function in a variety of basic cellular quality control and maintenance processes, such as proper folding of newly synthesized proteins, along with preventing protein misfolding and aggregation through the binding of exposed hydrophobic residues.

p(FPLX:HSPA) increases bp(GO:"'de novo' protein folding") View Subject | View Object

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p(FPLX:HSPA) decreases bp(HBP:misfolding) View Subject | View Object

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p(FPLX:HSPA) decreases a(MESH:"Protein Aggregates") View Subject | View Object

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Evidence 66356df198
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Multiple studies in model systems demonstrate that overexpression of HSP70 can reduce toxicity and protein aggregation.

p(FPLX:HSPA) decreases a(MESH:"Protein Aggregates") View Subject | View Object

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p(FPLX:HSPA) decreases path(HBP:proteotoxicity) View Subject | View Object

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Evidence 6c219fa8f3
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Although HSP70 was not identified as a modifier of α -synuclein in the screen studies we selected, directed overexpression of HSP70 has been shown to reduce α -synuclein-related proteotoxicity, supporting a central role for HSP70 in diseases of protein misfolding (Auluck et al., 2002).

p(FPLX:HSPA) decreases path(HBP:proteotoxicity) View Subject | View Object

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p(FPLX:HSPA) decreases a(HBP:"alpha-synuclein aggregates") View Subject | View Object

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Evidence 4ecf45a642
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Early studies demonstrated that overexpression of a specific human HSP70 (HSPA1L) in a Drosophila disease model suppressed neurodegeneration associated with expression of polyQ-containing forms of both ataxin 3 or androgen receptor, and α -synuclein (Warrick et al., 1999; Chan et al., 2000, 2002; Auluck et al., 2002).

p(HGNC:AR, var("?")) association path(HP:Neurodegeneration) View Subject | View Object

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p(HGNC:ATXN3, var("?")) association path(HP:Neurodegeneration) View Subject | View Object

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p(HGNC:HSPA1L) decreases path(HP:Neurodegeneration) View Subject | View Object

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p(HGNC:SNCA, var("?")) association path(HP:Neurodegeneration) View Subject | View Object

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path(HP:Neurodegeneration) association p(HGNC:ATXN3, var("?")) View Subject | View Object

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path(HP:Neurodegeneration) association p(HGNC:AR, var("?")) View Subject | View Object

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path(HP:Neurodegeneration) association p(HGNC:SNCA, var("?")) View Subject | View Object

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Evidence c29f61aebf
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Therapeutic approaches to overcome proteostasis deficiencies have largely focused on the activation of HSF1, the heat shock transcription factor responsible for simultaneous upregulation of the expression of multiple molecular chaperones during stress (Calamini et al., 2011; Pierce et al., 2013).

p(HGNC:HSF1) increases bp(HBP:Proteostasis) View Subject | View Object

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Evidence d2b7a382f4
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In addition to co-chaperones, overexpression of the human sHSP (HSPB7), a Caenorhabditis elegans HSP100 homolog (tor-2), and the yeast HSP60 subunit (CCT-1) and HSP90 homolog (HSP82) reduced toxicity and aggregation (Cao et al., 2005; Tam et al., 2006; Liang et al., 2008; Vos et al., 2010).

p(HGNC:HSPB7) decreases path(HBP:proteotoxicity) View Subject | View Object

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p(HGNC:HSPB7) decreases a(MESH:"Protein Aggregates") View Subject | View Object

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p(UNIPROT:P02829) decreases path(HBP:proteotoxicity) View Subject | View Object

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p(UNIPROT:P02829) decreases a(MESH:"Protein Aggregates") View Subject | View Object

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p(UNIPROT:P12612) decreases path(HBP:proteotoxicity) View Subject | View Object

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p(UNIPROT:P12612) decreases a(MESH:"Protein Aggregates") View Subject | View Object

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p(UNIPROT:Q9XXG5) decreases path(HBP:proteotoxicity) View Subject | View Object

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p(UNIPROT:Q9XXG5) decreases a(MESH:"Protein Aggregates") View Subject | View Object

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Evidence d1478bd4ab
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For example, overexpression of the human TPR domain-containing co- chaperone CHIP suppresses neurodegeneration in fly models expressing polyQ-containing versions of ataxin 1 and the N-terminal huntingtin fragment (Al-Ramahi et al., 2006).

p(HGNC:STUB1) decreases path(HP:Neurodegeneration) View Subject | View Object

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Evidence 7d7d1f9bd9
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HSP40s play a fundamental role as part of the HSP70-HSP40 system, as co-chaperones, stimulating HSP70 ATP hydrolysis (Fig. 3) (Kampinga and Craig, 2010; Kakkar et al., 2014).

p(HGNCGENEFAMILY:"DNAJ (HSP40) heat shock proteins") increases act(p(FPLX:HSPA), ma(GO:"ATPase activity")) View Subject | View Object

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Evidence 0fb2b1cb10
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Likewise, overexpression of the yeast TPR-domain-containing co- chaperone STI1 suppresses toxicity in a yeast model expressing the expanded huntingtin fragment (Wolfe et al., 2013).

p(UNIPROT:P15705) decreases path(HBP:proteotoxicity) View Subject | View Object

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Evidence 61c15f0b42
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The co- chaperone HSP40 (dHdj-1 and SIS1) and the nucleotide exchange factor SSE1 that specifically modulate HSP70 activity were also shown to suppress toxicity and aggregation in yeast and fly disease models (Chan et al., 2000; Krobitsch and Lindquist, 2000; Sadlish et al., 2008).

p(UNIPROT:P32589) regulates act(p(FPLX:HSPA)) View Subject | View Object

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p(UNIPROT:P32589) decreases path(HBP:proteotoxicity) View Subject | View Object

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p(UNIPROT:P32589) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

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Evidence ae81370526
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Among repressed genes, HSP40s were found to show significant changes as a family, with 62% of overall 48 HSP40 family members repressed in aging brain (superior frontal gyrus), 51% repressed in AD, and 41% repressed in both aging and AD.

path(MESH:"Alzheimer Disease") decreases p(HGNCGENEFAMILY:"DNAJ (HSP40) heat shock proteins") View Subject | View Object

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