Clabough, E.B.D., Aspili, C., Fussy, W.S., Ingersoll, J.D., Kislyakov, A., Li, E.S., Su, M.J., Wiles, D.B., Watson, T.E., Willy, A.J., Thomas Vinyard, H., Mollica Iii, P.J., Taylor, J.V., Smith, C.W., Roark, D.A., Tabrani, Z.P., Thomas, H.L., Shin, M., Venton, B.J., Hayes, D., Sipe, C.W. (2023). Huntingtin Plays a Role in the Physiological Response to Ethanol in Drosophila.  J. Huntingtons Dis. 12(3): 241--252.

FBrf0257740

Research paper

Huntingtin (htt) protein is an essential regulator of nervous system function through its various neuroprotective and pro-survival functions, and loss of wild-type htt function is implicated in the etiology of Huntington's disease. While its pathological role is typically understood as a toxic gain-of-function, some neuronal phenotypes also result from htt loss. Therefore, it is important to understand possible roles for htt in other physiological circumstances. To elucidate the role of htt in the context of ethanol exposure, we investigated how loss of htt impacts behavioral and physiological responses to ethanol in Drosophila. We tested flies lacking htt for ethanol sensitivity and tolerance, preference for ethanol using capillary feeder assays, and recovery of mobility after intoxication. Levels of dopamine neurotransmitter and numbers of dopaminergic cells in brains lacking dhtt were also measured. We found that dhtt-null flies are both less sensitive and more tolerant to ethanol exposure in adulthood. Moreover, flies lacking dhtt are more averse to alcohol than controls, and they recover mobility faster following acute ethanol intoxication. We showed that dhtt mediates these effects at least in part through the dopaminergic system, as dhtt is required to maintain normal levels of dopamine in the brain and normal numbers of dopaminergic cells in the adult protocerebrum. Our results demonstrate that htt regulates the physiological response to ethanol and indicate a novel neuroprotective role for htt in the dopaminergic system, raising the possibility that it may be involved more generally in the response to toxic stimuli.