Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation

Abstract

We sought novel strategies to reduce levels of the polyglutamine androgen receptor (polyQ AR) and achieve therapeutic benefits in models of spinobulbar muscular atrophy (SBMA), a protein aggregation neurodegenerative disorder. Proteostasis of the polyQ AR is controlled by the Hsp90/Hsp70-based chaperone machinery, but mechanisms regulating the protein’s turnover are incompletely understood. We demonstrate that overexpression of Hip, a co-chaperone that enhances binding of Hsp70 to its substrates, promotes client protein ubiquitination and polyQ AR clearance. Furthermore, we identify a small molecule that acts similarly to Hip by allosterically promoting Hsp70 binding to unfolded substrates. Like Hip, this synthetic co-chaperone enhances client protein ubiquitination and polyQ AR degradation. Both genetic and pharmacologic approaches targeting Hsp70 alleviate toxicity in a Drosophila model of SBMA. These findings highlight the therapeutic potential of allosteric regulators of Hsp70, and provide new insights into the role of the chaperone machinery in protein quality control.

pH-induced molecular shedding drives the formation of amyloid fibril-derived oligomers

“…Hsp70 has been shown to inhibit aggregation and toxicity of a variety of amyloidogenic systems via distinct mechanisms (28)(29)(30). Here we show that hsp70 is able to protect cells against the deleterious effects of β 2 m fibril-mediated cell dysfunction to a greater extent than chemical cross-linking.…”

“…To determine whether fibrilinduced membrane damage can be inhibited by enhancing the kinetic stability of β 2 m amyloid fibrils, the molecular chaperone hsp70 was added. Previous studies have shown that the association of hsp70 (or its constitutively expressed homolog, hsc70) with amyloid aggregates protects against amyloid toxicity (28)(29)(30). Recombinant hsp70-1A (29) was incubated with β 2 m amyloid fibrils at pH 6.4 in a 1:0.25 or 1:3 molar ratio (monomer equivalent β 2 m:chaperone) and the effect of the chaperone on fibril stability was measured using ThT fluorescence.…”

Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures

“…Studies with the small molecule geldanamycin (GA), a potent inhibitor of Hsp90 ATPase activity, have revealed that increases in the levels of molecular chaperones such as Hsp70 or Hsp40 are associated with reduced aggregation and toxicity of mutant HTTex1 fragments in cells and flies [36]. The importance of chaperone networks in managing misfolded proteins in cells is also supported by the effect of the compound YM-1, which increases the binding affinity of Hsp70 to polyQ disease proteins, leading to an increased efficiency of their ubiquitination and degradation [37]. High-throughput screenings have led to the identification of numerous novel small molecules that influence the expression of molecular chaperones in mammalian cells [38].…”

Spinal bulbar muscular atrophy, an inherited neurodegenerative disease: Potential mechanisms and therapeutic targets

“…However, trails using antiandrogen therapy, commonly used in the treatment of advanced prostate cancer, yielded disappointing findings, despite highly promising animal studies. Other studies have shown AR:HSP70 complex and small molecules such as trehalose as a potential therapeutic target for SBMA [25,28]. Based on these studies, a potential therapeutic model can be proposed (Figure 2).…”