Key result
Withaferin A treatment significantly increased the average lifespan of Huntington's disease mice by approximately 25 days and reduced nuclear aggregates by 40-50% compared to vehicle treatment.
Why the study?
Impairment of the proteostasis network and mutant huntingtin aggregation characterize Huntington's disease, but strategies targeting heat shock response to rescue proteostasis needed investigation.
Withaferin A delays disease progression, reduces mutant huntingtin aggregation, and extends lifespan in a mouse model of Huntington's disease by activating the heat shock response.
Should not yet change clinical practice in Huntington's disease; extends animal model evidence for Withaferin A.
Impairment of proteostasis network is one of the characteristic features of many age-related neurodegenerative disorders including autosomal dominantly inherited Huntington’s disease (HD). In HD, N-terminal portion of mutant huntingtin protein containing expanded polyglutamine repeats accumulates as inclusion bodies and leads to progressive deterioration of various cellular functioning including proteostasis network. Here we report that Withaferin A (a small bioactive molecule derived from Indian medicinal plant, Withania somnifera ) partially rescues defective proteostasis by activating heat shock response (HSR) and delay the disease progression in a HD mouse model. Exposure of Withaferin A activates HSF1 and induces the expression of HSP70 chaperones in an in vitro cell culture system and also suppresses mutant huntingtin aggregation in a cellular model of HD. Withaferin A treatment to HD mice considerably increased their lifespan as well as restored progressive motor behavioural deficits and declined body weight. Biochemical studies confirmed the activation of HSR and global decrease in mutant huntingtin aggregates load accompanied with improvement of striatal function in Withaferin A treated HD mice brain. Withaferin A treated HD mice also exhibit significant decrease in inflammatory processes as evident from the decreased microglial activation. These results indicate immense potential of Withaferin A for the treatment of HD and related neurodegenerative disorders involving protein misfolding and aggregation.
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Joshi et al. (2021) studied Huntington's disease. Withaferin A vs. Vehicle (saline with 5% DMSO) was evaluated on Average lifespan. Withaferin A treatment significantly increased the average lifespan of Huntington's disease mice by approximately 25 days and reduced nuclear aggregates by 40-50% compared to vehicle treatment.
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