PubMed: 27491084

Model systems of protein-misfolding diseases reveal chaperone modifiers of proteotoxicity.
Disease models & mechanisms
Brehme M | Voisine C

Evidence 803ac26b46

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).

Evidence 52edaaf083

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

Evidence ad8c43f332

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).

Evidence 1a2584be89

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).

Evidence 55c578542a

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

Evidence c7298d4d26

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.

Evidence 2337fbbcbc

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).

Evidence 6e859aab60

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.

Evidence b4394f828e

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;)

Evidence fbbb245cfe

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

Evidence e967bd058c

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.

Evidence 66356df198

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

Evidence 6c219fa8f3

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).

Evidence 4ecf45a642

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).

Evidence c29f61aebf

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).

Evidence d2b7a382f4

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).

Evidence d1478bd4ab

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).

Evidence 7d7d1f9bd9

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).

Evidence 0fb2b1cb10

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).

Evidence 61c15f0b42

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).

Evidence ae81370526

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.


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