Affiliation:
1. Jawaharlal Nehru Centre for Advanced Scientific Research 1 Evolutionary and Integrative Biology Unit , , Bangalore 560064 , India
2. Jawaharlal Nehru Centre for Advanced Scientific Research 2 Neuroscience Unit , , Bangalore 560064 , India
Abstract
ABSTRACT
Circadian disturbances are early features of neurodegenerative diseases, including Huntington's disease (HD). Emerging evidence suggests that circadian decline feeds into neurodegenerative symptoms, exacerbating them. Therefore, we asked whether known neurotoxic modifiers can suppress circadian dysfunction. We performed a screen of neurotoxicity-modifier genes to suppress circadian behavioural arrhythmicity in a Drosophila circadian HD model. The molecular chaperones Hsp40 and HSP70 emerged as significant suppressors in the circadian context, with Hsp40 being the more potent mitigator. Upon Hsp40 overexpression in the Drosophila circadian ventrolateral neurons (LNv), the behavioural rescue was associated with neuronal rescue of loss of circadian proteins from small LNv soma. Specifically, there was a restoration of the molecular clock protein Period and its oscillations in young flies and a long-lasting rescue of the output neuropeptide Pigment dispersing factor. Significantly, there was a reduction in the expanded Huntingtin inclusion load, concomitant with the appearance of a spot-like Huntingtin form. Thus, we provide evidence implicating the neuroprotective chaperone Hsp40 in circadian rehabilitation. The involvement of molecular chaperones in circadian maintenance has broader therapeutic implications for neurodegenerative diseases.
This article has an associated First Person interview with the first author of the paper.
Funder
Department of Science and Technology, Ministry of Science and Technology, India
Council for Scientific and Industrial Research, Human Resource Development Group
Jawaharlal Nehru Centre for Advanced Scientific Research
Publisher
The Company of Biologists
Subject
General Biochemistry, Genetics and Molecular Biology,Immunology and Microbiology (miscellaneous),Medicine (miscellaneous),Neuroscience (miscellaneous)
Cited by
2 articles.
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