Flanking domain stability modulates the aggregation kinetics of a polyglutamine disease protein

Helen Saunders, Dimitri Gilis, Marianne Rooman, Yves Dehouck, Amy Robertson, Stephen Bottomley

Research output: Contribution to journalArticleResearchpeer-review

32 Citations (Scopus)


Spinocerebellar Ataxia Type 3 (SCA3) is one of nine polyglutamine (polyQ) diseases that are all characterized by progressive neuronal dysfunction and the presence of neuronal inclusions containing aggregated polyQ protein, suggesting that protein misfolding is a key part of this disease. Ataxin-3, the causative protein of SCA3, contains a globular, structured N-terminal domain (the Josephin domain) and a flexible polyQ-containing C-terminal tail, the repeat-length of which modulates pathogenicity. It has been suggested that the fibrillogenesis pathway of ataxin-3 begins with a non-polyQ dependent step mediated by Josephin domain interactions, followed by a polyQ dependent step. To test the involvement of the Josephin domain in ataxin-3 fibrillogenesis, we have created both pathogenic and non-pathogenic length ataxin-3 variants with a stabilized Josephin domain, and have both stabilized and destabilized the isolated Josephin domain. We show that changing the thermodynamic stability of the Josephin domain modulates ataxin-3 fibrillogenesis. These data support the hypothesis that the first stage of ataxin-3 fibrillogenesis is caused by interactions involving the non-polyQ containing Josephin domain and that the thermodynamic stability of this domain is linked to the aggregation propensity of ataxin-3.
Original languageEnglish
Pages (from-to)1675 - 1681
Number of pages7
JournalProtein Science
Issue number10
Publication statusPublished - 2011

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