Polyglutamine expansion of ataxin-3 alters its degree of ubiquitination and phosphorylation at specific sites

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Ubiquitination and phosphorylation of proteins represent post translational modifications (PTMs) capable of regulating a variety of cellular processes. In the neurodegenerative disorder spinocerebellar ataxia type 3 (SCA3), the disease causing protein ataxin-3 carries an expanded polyglutamine (polyQ) stretch causing it to aggregate in nuclear inclusions. These inclusions are decorated with ubiquitin suggestive of a malfunction in the clearance of the mutant protein. Differences in ubiquitin chain topology between normal and polyQ expanded ataxin-3 could be involved in the differential clearance of the two proteins and play a role in SCA3 pathogenesis. Likewise, changes in phosphorylation patterns between the two variants could contribute to pathogenic processes involved in SCA3. We therefore determined the ubiquitination and phosphorylation patterns, together with the ubiquitin-linkage types associated with normal and polyQ expanded ataxin-3 by mass spectrometry (MS). This analysis revealed a similar ubiquitin linkage pattern on normal and expanded ataxin-3. However, the distribution of ubiquitinated lysine residues was altered in polyQ expanded ataxin-3, with increased ubiquitination at the new identified ubiquitination site lysine-8. MS analysis of phosphorylation also revealed novel phosphorylation sites in ataxin-3, and an increase in phosphorylation of expanded ataxin-3 at several positions. The study suggests that differences in clearance of normal and expanded ataxin-3 are not attributed to differences in ubiquitin-linkage pattern. However, the observed differences between the normal and polyQ expanded ataxin-3 with respect to the degree of ubiquitination and phosphorylation on specific sites may have an impact on ataxin-3 function and SCA3 pathogenesis.

OriginalsprogEngelsk
TidsskriftNeurochemistry International
Vol/bind105
Sider (fra-til)42-50
Antal sider9
ISSN0197-0186
DOI
StatusUdgivet - maj 2017

ID: 178483519