Suppression of polyglutamine protein toxicity by co-expression of a heat-shock protein 40 and a heat-shock protein 110

Abstract

A network of heat-shock proteins mediates cellular protein homeostasis, and has a fundamental role in preventing aggregation-associated neurodegenerative diseases. In a Drosophila model of polyglutamine (polyQ) disease, the HSP40 family protein, DNAJ-1, is a superior suppressor of toxicity caused by the aggregation of polyQ containing proteins. Here, we demonstrate that one specific HSP110 protein, 70 kDa heat-shock cognate protein cb (HSC70cb), interacts physically and genetically with DNAJ-1 in vivo, and that HSC70cb is necessary for DNAJ-1 to suppress polyglutamine-induced cell death in Drosophila. Expression of HSC70cb together with DNAJ-1 significantly enhanced the suppressive effects of DNAJ-1 on polyQ-induced neurodegeneration, whereas expression of HSC70cb alone did not suppress neurodegeneration in Drosophila models of either general polyQ disease or Huntington's disease. Furthermore, expression of a human HSP40, DNAJB1, together with a human HSP110, APG-1, protected cells from polyQ-induced neural degeneration in flies, whereas expression of either component alone had little effect. Our data provide a functional link between HSP40 and HSP110 in suppressing the cytotoxicity of aggregation-prone proteins, and suggest that HSP40 and HSP110 function together in protein homeostasis control.

Extended survival of misfolded G85R SOD1-linked ALS mice by transgenic expression of chaperone Hsp110

“…Addition of G85R SOD1YFP to squid axoplasm inhibits anterograde axonal vesicle transport, but purified human Hsp110 (HspA4L) prevents this effect even when added at substoichiometric amounts relative to the misfolded protein, suggesting that it cooperates with endogenous Hsc70 and DnaJ homologs to dissociate toxic oligomeric forms (21). In studies in Drosophila eye, transgenic expression of either Drosophila Hsp110 or human Hsp110 (HspA4L; APG1) was able to rescue toxicity from coexpressed polyQ-expanded proteins (22,23). As mentioned, in motor neurons of the G85R SOD1YFP line, one of three endogenous mouse Hsp110 RNAs, HspH1, is induced approximately twofold compared with wtSOD1YFP motor neurons, one of the few RNAs observed to be altered (3).…”

Reversing deleterious protein aggregation with re-engineered protein disaggregases

“…29 We recently expressed Hsp70 or Hsp104 in a Drosophila model of spinocerebellar ataxia. 14 Here, Hsp104 suppressed toxicity after the onset of polyglutamine-induced degeneration.…”

Drosophila as an In Vivo Model for Human Neurodegenerative Disease

“…They illustrate how molecular genetic approaches can assess whether up-and downregulation of target genes of special interest can modulate the toxicity of a disease protein and thereby contribute to disease progression. These and other studies have revealed a number of effects of various molecular chaperone proteins, chaperone helper proteins, and protein quality control pathways on disease pathogeneisis in fly models (Warrick et al 1999;Chan et al 2000;KazemiEsfarjani and Benzer 2000;Vos et al 2010;Kuo et al 2013). These studies have also revealed links between the ubiquitin-proteasome pathway and autophagy pathways, as these processes dynamically interact in vivo to affect protein degradation, normally and in disease (Pandey et al 2007).…”