α Pix enhances mutant huntingtin aggregation

Abstract

Huntington's disease is caused by polyglutamine-expanded mutant huntingtin (muhtt), an aggregation-prone protein. We identified the Pak-interacting exchange factor (α Pix/Cool2) as a novel huntingtin (htt) interacting protein, after screening actin-cytoskeleton organization-related factors. Using immunoprecipitation experiments, we show that α Pix binds to both the N-terminal of wild-type htt (wthtt) and mutant htt (muthtt). Colocalization studies revealed that α Pix accumulates in muthtt aggregates. Deletion analysis suggested that the dbl homology (DH) and pleckstrin homology (PH) domains of α Pix are required for its interaction with htt. Overexpression of α Pix enhanced muthtt aggregation by inducing SDS-soluble muthtt–muthtt interactions. Conversely, knocking down α Pix attenuated muhtt aggregation. These findings suggest that α Pix plays an important role in muthtt aggregation.