Combating Parkinson’s disease-associated toxicity by modulating proteostasis

The incidence of age-associated neurodegenerative disease is growing rapidly, and it is expected to triple by 2050 (1). Currently, there are no cures or treatments that significantly modify disease progression. As researchers develop an in-depth understanding of the mechanisms of neurodegeneration, common features across different diseases are becoming apparent. Chief among them is the presence of protein aggregates, such as amyloid plaques and tau tangles in Alzheimer’s disease (2); α-synuclein–rich Lewy bodies and Lewy neurites in Parkinson’s disease (3); huntingtin aggregates in Huntington’s disease (4); and aggregates of superoxide dismutase 1 (SOD1), TDP43, and FUS in amyotrophic lateral sclerosis (5). Although the precise mechanisms of protein aggregation-associated toxicity remain unclear, the accumulation of aggregated proteins in the diseased neurons indicates imbalances in protein homeostasis (proteostasis(definition)) (proteostasis is reviewed in ref. 6). As such, researchers are studying the potential therapeutic strategy of restoring proteostasis to normal levels by boosting the activity of molecular chaperones. One way to do so is to activate HSF1 (heat shock factor protein 1) by inhibiting HSP90 (heat shock protein 90), thereby stimulating the expression of multiple chaperones. Indeed, this strategy has been shown to be effective in fly models of Parkinson’s disease … [↵][1]1To whom correspondence should be addressed. Email: qqhoang{at}iu.edu. [1]: #xref-corresp-1-1