Polyglutamine-expanded ataxin-3: a target engagement marker for Spinocerebellar ataxia type 3 in peripheral blood

Abstract Spinocerebellar ataxia type 3 is a rare neurodegenerative disease, caused by a CAG repeat expansion leading to polyglutamine elongation in the ataxin-3 protein. While no curative therapy is yet available, preclinical gene silencing approaches to reduce polyglutamine-toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers. We developed a novel ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid. Statistical analyses revealed a correlation with clinical parameters and a stability of polyglutamine-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phase.