Cross-seeding fibrillation of Q/N-rich proteins offers new pathomechanism of polyglutamine diseases

Yoshiaki Furukawa, Kumi Kaneko, Gen Matsumoto, Masaru Kurosawa, Nobuyuki Nukina

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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 dysregula-tion 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.

Original languageEnglish
Pages (from-to)5153-5162
Number of pages10
JournalJournal of Neuroscience
Volume29
Issue number16
DOIs
Publication statusPublished - 2009 Apr 22

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ASJC Scopus subject areas

  • Neuroscience(all)

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