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

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Netherlands NLM ID: 0375403 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-5883 (Electronic) Linking ISSN: 0022510X NLM ISO Abbreviation: J Neurol Sci Subsets: MEDLINE
    • Publication Information:
      Original Publication: Amsterdam : Elsevier, <19 ->
    • Subject Terms:
      Machado-Joseph Disease*/genetics ; Neurodegenerative Diseases*; Animals ; Humans ; Ataxin-3/genetics ; Drosophila ; Lysine/genetics ; Ubiquitin
    • Abstract:
      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.)
    • Comments:
      Update of: bioRxiv. 2023 Jun 01:2023.05.30.542896. doi: 10.1101/2023.05.30.542896. (PMID: 37398109)
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    • Grant Information:
      R01 NS086778 United States NS NINDS NIH HHS; T34 GM140932 United States GM NIGMS NIH HHS
    • Contributed Indexing:
      Keywords: Aggregation; Ataxia; Deubiquitinase; Polyglutamine; Ubiquitin
    • Accession Number:
      EC 3.4.19.12 (Ataxin-3)
      K3Z4F929H6 (Lysine)
      0 (Ubiquitin)
    • Publication Date:
      Date Created: 20231021 Date Completed: 20231127 Latest Revision: 20241116
    • Publication Date:
      20241116
    • Accession Number:
      PMC10841544
    • Accession Number:
      10.1016/j.jns.2023.120828
    • Accession Number:
      37865002