Lysine 117 on ataxin-3 modulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3.

Autor: Blount JR; Department of Pharmacology, Wayne State University, United States of America., Patel NC; Department of Pharmacology, Wayne State University, United States of America., Libohova K; Department of Pharmacology, Wayne State University, United States of America., Harris AL; Department of Pharmacology, Wayne State University, United States of America; Maximizing Access to Research Careers, Wayne State University, United States of America., Tsou WL; Department of Pharmacology, Wayne State University, United States of America., Sujkowski A; Department of Pharmacology, Wayne State University, United States of America. Electronic address: asujkows@med.wayne.edu., Todi SV; Department of Pharmacology, Wayne State University, United States of America; Maximizing Access to Research Careers, Wayne State University, United States of America; Department of Neurology, Wayne State University, United States of America. Electronic address: stodi@wayne.edu.
Jazyk: angličtina
Zdroj: Journal of the neurological sciences [J Neurol Sci] 2023 Nov 15; Vol. 454, pp. 120828. Date of Electronic Publication: 2023 Oct 05.
DOI: 10.1016/j.jns.2023.120828
Abstrakt: Ataxin-3 (Atxn3) is a deubiquitinase with a polyglutamine (polyQ) repeat tract whose abnormal expansion causes the neurodegenerative disease, Spinocerebellar Ataxia Type 3 (SCA3; also known as Machado-Joseph Disease). The ubiquitin chain cleavage properties of Atxn3 are enhanced when the enzyme is itself ubiquitinated at lysine (K) at position 117: in vitro, K117-ubiqutinated Atxn3 cleaves poly-ubiquitin markedly more rapidly compared to its unmodified counterpart. How polyQ expansion causes SCA3 remains unclear. To gather insights into the biology of disease of SCA3, here we posited the question: is K117 important for toxicity caused by pathogenic Atxn3? To answer this question, we generated transgenic Drosophila lines that express full-length, human, pathogenic Atxn3 with 80 polyQ with an intact or mutated K117. We found that mutating K117 mildly enhances the toxicity and aggregation of pathogenic Atxn3. An additional transgenic line that expresses Atxn3 without any K residues confirms increased aggregation of pathogenic Atxn3 whose ubiquitination is perturbed. These findings suggest that Atxn3 ubiquitination is a regulatory step of SCA3, in part by modulating its aggregation.
Competing Interests: Declaration of Competing Interest The authors declare that they do not have any conflicts of interest to disclose.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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