Abstract
A pathological hallmark of the Huntington's disease (HD) is intracellular inclusions containing a huntingtin (Htt) protein with an elongated polyglutamine tract. Aggregation of mutant Htt causes abnormal protein-protein interactions, and the functional dysregulation of aggregate-interacting proteins (AIPs) has been proposed as a pathomechanism of HD. Despite this, a molecular mechanism remains unknown how Htt aggregates sequester AIPs. We note an RNA-binding protein, TIA-1, as a model of AIPs containing a Q/N-rich sequence and suggest that in vitro and in vivo Htt fibrillar aggregates function as a structural template for inducing insoluble fibrillation of TIA-1. It is also plausible that such a cross-seeding activity of Htt aggregates represses the physiological function of TIA-1. We thus propose that Htt aggregates act as an intracellular hub for the cross-seeded fibrillation of Q/N-rich AIPs and that a cross-seeding reaction is a molecular origin to cause diverse pathologies in a polyglutamine disease.