Genetics of Alcohol Abuse – from Flies to Humans

Graphic- Genetics of Alcohol Abuse – from Flies to Humans
In the fly liquid-food interaction counter assay, flies choose between liquid sugar with (left) or without (right) 15% alcohol, yielding a measure for flies’ alcohol preference.

Genetic factors play a major role in the development of human alcohol use disorder. The fruit fly, Drosophila melanogaster, has been used as a model organism to isolate and characterize genes in many physiological disorders. Like many humans, flies initially dislike alcohol, but develop a taste for it with continued experience. In an unbiased screen, the lab directed by Adrian Rothenfluh, PhD, isolated flies lacking a certain gene (Rsu1) that produces a strong liking for alcohol, even before repeated exposure. Their investigations in Drosophila showed that Rsu1 and downstream signaling molecules regulate actin dynamics; genetic manipulations that increase actin filament turnover lead to accelerated development of alcohol preference, while manipulations that increase actin filament stability abolish the development of preference. Furthermore, they showed that variants of the human Rsu1 gene are associated with altered drinking behavior and with changes in brain activity after receiving a reward. Together, these findings show the power of unbiased approaches in model organisms to generate insights that can be translated to humans to advance scientific understanding of the genetic mechanisms driving alcohol use disorder. 

References:

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Rsu1 regulates ethanol consumption in drosophila and humans.  Ojelade SA, Jia T, Rodan AR, Chenyang T, Kadrmas JL, Cattrell A, Ruggeri B, Charoen P, Lemaitre H, Banaschewski T, Büchel C, Bokde ALW, Carvalho F, Conrod F, Flor H, Frouin V, Gallinat J, Garavan H, Gowland PA, Heinz A, Ittermann B, Lathrop M, Lubbe S, Martinot JL, Paus T, Smolka MN, Spanagel R, O’Reilly PF, Laitinen J, Veijola JM, Feng J, Desrivières S, Jarvelin MR, Schumann G, Rothenfluh A. Proc. Natl. Acad. Sci. U.S.A. 2015 Jul;112(30):E4085  

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Altered actin filament dynamics in the drosophila mushroom bodies lead to fast acquisition of alcohol consumption preference. Butts AR, Ojelade SA, Pronovost ED, Seguin A, Merrill CB, Rodan AR, Rothenfluh A. J Neurosci. 2019 Nov 6;39(45):8877.

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U of U Health Key Faculty Collaborators

Aylin Rodan, PhD, MD
Julie Kadrmas, PhD 
Mary Beckerle, PhD