Studying the role of huntingtin in Drosophila clock neurons

ANA RICCIUTI; NARA I. MURARO

Zurich

Congreso; Swiss Drosophila Meeting 2021; 2021

One of the hallmarks of polyglutamine (polyQ) diseases is the selective vulnerabilityof neurons in spite of ubiquitous expression of the pathogenic protein. It has beenreported that the two circadian clusters of lateral ventral neurons (LNv) ofDrosophila respond differently to the elongation of the polyQ tract of huntingtin (Htt)protein and, while HttpolyQ protein functionally ablates the small LNvs (sLNvs)subgroup, the large LNvs (lLNV) remain unaltered. Our goal is to explore thisdifferential response. To this end we took a double and complementary approach:the overexpression of the human Htt protein and the downregulation of theDrosophila Htt protein (dHtt) in the LNvs, and assessed the morphological effectsand behavioural consequences on the outputs these neurons command: circadianrhythms and sleep. Our results regarding the morphology of the LNvs underHttpolyQ expression in young flies fit well with the published literature: sLNvspresent protein accumulations of HttpolyQ and lLNvs do not. However, in aged flieslLNvs also show HttpolyQ protein aggregation, both in the somas and on theirprojections. These results suggest that, although the reported differential sensibilitybetween the two neuronal groups exists, lLNvs are not immune to HttpolyQ proteinaggregation. Finally, we found that downregulation of dHtt in the sLNvs led toarrhythmic flies in constant conditions. An increased and more consolidated sleepwas also observed following this manipulation.