Abstract
The mechanism underlying the role of Hsp70s in toxicity associated with intracellular accumulation of toxic protein inclusions is under intense investigation. In current study, we examined the roles of all different isoforms of yeast cytosolic Ssa Hsp70 on α-synuclein mediated cellular toxicity. The study showed that yeast cells expressing stress-inducible Ssa3 or Ssa4 as sole Ssa Hsp70 isoforms, reduced α-synuclein toxicity better than those expressing a constitutive counterpart. The protective effect of stress-inducible Ssa Hsp70s was not α-syn specific, but more general to other inclusion forming proteins such as polyQ. We show that the protective effect is not by induction of a general stress response in Ssa3 cells rather by promoting α-synuclein degradation through autophagy. The present study revealed that effect of Hsp70s was isoform dependent, and that autophagy protects Ssa3 cells from the deleterious effects of toxic protein inclusions.
Highlights
Accumulation of protein inclusions is associated with various human diseases, such as neurodegenerative diseases and type 2 diabetes
The Hsp70 chaperones has emerged as potent suppressor of toxicity caused by protein inclusions such as those formed of α-synuclein and polyQ
The underlying mechanism of Hsp70 mediated effect remains unclear, and it is believed that anti-aggregation activity of Hsp70 reduces protein inclusion mediated toxicity
Summary
Accumulation of protein inclusions is associated with various human diseases, such as neurodegenerative diseases and type 2 diabetes. As formation of protein inclusion involves conformational changes in proteins, various chaperones have been extensively studied for their role in the process. The Hsp family of proteins have emerged as promising candidates to protect cells from amyloid-associated toxicity. The ubiquitin-proteasome system (UPS) and autophagy are two major cellular degradation pathways, with autophagy being more specific for long-lived proteins or larger aggregates [7, 8]. In addition to their primary function of preventing protein aggregation, the role of chaperones in directing terminally misfolded proteins to either proteasome or autophagy is well established [9], [10]
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