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bioRxiv · 10.1101/2021.12.27.474320

HSP40 overexpression in pacemaker neurons protects against circadian dysfunction in a Drosophila model of Huntington's Disease

Prakash, P.·Pradhan, A. K.·Sheeba, V.
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Abstract

Circadian disturbances are early features of neurodegenerative diseases, including Huntingtons Disease (HD), affecting the quality of life of patients and caregivers. Emerging evidence suggests that circadian decline feeds-forward to neurodegenerative symptoms, exacerbating them, highlighting a need for restoring circadian health. Therefore, we asked whether any of the 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. Notably, the molecular chaperones HSP40 and HSP70 (Heat Shock Protein) emerged as significant suppressors in the circadian context, with HSP40 being the more potent mitigator of HD-induced deficits. Upon HSP40 overexpression in the Drosophila circadian ventrolateral neurons (LNv), the behavioural rhythm rescue was associated with neuronal rescue of loss in 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 for the first time that implicates the neuroprotective chaperone HSP40 in circadian rehabilitation. Given the importance of proteostasis and circadian health in neurodegenerative diseases, the involvement of molecular chaperones in circadian maintenance has broader therapeutic implications. Summary StatementThis study shows, for the first time, a neuroprotective role of chaperone HSP40 in overcoming circadian dysfunction associated with Huntingtons Disease in a Drosophila model

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Prakash, P., Pradhan, A. K., Sheeba, V.. 2021-12-28. HSP40 overexpression in pacemaker neurons protects against circadian dysfunction in a Drosophila model of Huntington's Disease. https://doi.org/10.1101/2021.12.27.474320

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