Implications of specific lysine residues within ataxin-3 for the molecular pathogenesis of Machado-Joseph disease

Frontiers in Molecular Neuroscience

Molecular Neuroscience

Huu Phuc Nguyen¹  Thorsten Schmidt²  Sercan Bayezit²  Olaf Riess²  Rafael Saup²  Xiaoling Li²  Jaqueline Jung²  Priscila Pereira Sena²  Jonasz Jeremiasz Weber³  Rana Dilara Incebacak Eltemur³  Ana Velic⁴  Boris Macek⁴ 

[1] Department of Human Genetics, Ruhr University Bochum, Bochum, Germany;Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany;Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany;Department of Human Genetics, Ruhr University Bochum, Bochum, Germany;Proteome Center Tübingen, University of Tübingen, Tübingen, Germany;

关键词: Polyglutamine diseases;    spinocerebellar ataxia type 3;    protein aggregation;    proteasomal degradation;    deubiquitinase;    ataxin-3;    posttranslational modification;    ubiquitination;   

DOI  :  10.3389/fnmol.2023.1133271

 received in 2022-12-28, accepted in 2023-05-03,  发布年份 2023

来源: Frontiers

【 摘 要 】

Lysine residues are one of the main sites for posttranslational modifications of proteins, and lysine ubiquitination of the Machado-Joseph disease protein ataxin-3 is implicated in its cellular function and polyglutamine expansion-dependent toxicity. Despite previously undertaken efforts, the individual roles of specific lysine residues of the ataxin-3 sequence are not entirely understood and demand further analysis. By retaining single lysine residues of otherwise lysine-free wild-type and polyglutamine-expanded ataxin-3, we assessed the effects of a site-limited modifiability on ataxin-3 protein levels, aggregation propensity, localization, and stability. We confirmed earlier findings that levels of lysine-free ataxin-3 are reduced due to its decreased stability, which led to a diminished load of SDS-insoluble species of its polyglutamine-expanded form. The isolated presence of several single lysine residues within the N-terminus of polyglutamine-expanded ataxin-3 significantly restored its aggregate levels, with highest fold changes induced by the presence of lysine 8 or lysine 85, respectively. Ataxin-3 lacking all lysine residues presented a slightly increased nuclear localization, which was counteracted by the reintroduction of lysine 85, whereas presence of either lysine 8 or lysine 85 led to a significantly higher ataxin-3 stability. Moreover, lysine-free ataxin-3 showed increased toxicity and binding to K48-linked polyubiquitin chains, whereas the reintroduction of lysine 85, located between the ubiquitin-binding sites 1 and 2 of ataxin-3, normalized its binding affinity. Overall, our data highlight the relevance of lysine residues 8 and 85 of ataxin-3 and encourage further analyses, to evaluate the potential of modulating posttranslational modifications of these sites for influencing pathophysiological characteristics of the Machado-Joseph disease protein.

【 授权许可】

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Copyright © 2023 Pereira Sena, Weber, Bayezit, Saup, IncebacakEltemur, Li, Velic, Jung, Macek, Nguyen, Riess and Schmidt.