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The Journal of Neuroscience, April 22, 2009, 29(16):5153-5162; doi:10.1523/JNEUROSCI.0783-09.2009

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Neurobiology of Disease
Cross-Seeding Fibrillation of Q/N-Rich Proteins Offers New Pathomechanism of Polyglutamine Diseases

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

Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan

Correspondence should be addressed to Nobuyuki Nukina, Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Email: nukina{at}brain.riken.jp

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.

Received Feb. 16, 2009; accepted March 23, 2009.

Correspondence should be addressed to Nobuyuki Nukina, Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Email: nukina{at}brain.riken.jp






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