Identifying Molecular Pathways Linking Circadian Rhythms and Neurodegeneration

Xu, Fangke

doi:https://doi.org/10.21985/n2-c7cx-qm31

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Identifying Molecular Pathways Linking Circadian Rhythms and Neurodegeneration

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Neurodegenerative diseases (NDs) commonly involve the accumulation and aggregation of neurotoxic proteins that impair and ultimately destroy specific neurons. Considerable evidence from human and animal studies indicates that many NDs show disrupted circadian and sleep as symptoms. Yet little is known about the molecular mechanisms by which genes cause NDs could impair circadian rhythmicity. In addition, it is unknown if circadian clocks, in turn, can modulate ND pathogenesis. To address the relationship between circadian clocks and neurodegenerative diseases, we performed a large-scale screen of genetic ND models in Drosophila, and found a several, including mutant Htt (mHtt; for Huntington’s Disease; HD), TDP43/FUS (for amyotrophic lateral sclerosis; ALS) and mutant ATNX3 (for spinocerebellar ataxia type 3; SCA3), that display poor circadian rhythmicity when they are expressed in circadian neurons. These models display a range of molecular and cellular phenotypes from loss of neuropeptide expression and cell loss. To understand the basis of this poor rhythmicity, we analyzed the molecular and cellular impact of mHtt which resulted in poor behavioral rhythmicity and loss of a key subset of clock neurons. We also observed a dramatic reduction in the core clock component PERIOD. To determine if the clock-regulated mHtt effects, we examined cell loss under 10:10 cycles and found that this condition was neuroprotective but that this effect was gone in a perS mutant, confirming a role of circadian timing. Similarly, we observed neuroprotective effects in mutants of the core clock activator Clk which was suppressed in double mutants also lacking the CLK repressor, PER. Thus, circadian clocks are not only a target of mHtt but may also be an important player in mediating mHtt-mediated pathogenesis. To identify genes that mediate the effect of the clock on mHtt, we used a behavioral screen for HD suppressors, identifying clock-regulated genes that modify both pre-degenerative/functional and/or cell death effects of mHtt. As part of this screen, several novel pathways that mediate mHtt effects on behavior have been discovered including the RNA-binding protein encoded by Ataxin2 (Atx2), involved in multiple NDs, and a co-chaperon, encoded by Hsp70/90 Organizing Protein (Hop) which is involved in multiple NDs. Overall, these studies reveal the clock-regulated molecular and cellular pathways that link mHtt to clock disruption.

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