Abstract
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 nonpathogenic 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.