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- Title
Cross-Seeding Fibrillation of Q/N-Rich Proteins Offers New Pathomechanism of Polyglutamine Diseases.
- Authors
Furukawa, Yoshiaki; Kaneko, Kumi; Matsumoto, Gen; Kurosawa, Masaru; Nukina, Nobuyuki
- 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.Wenote 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.
- Subjects
HUNTINGTON disease; PROTEIN-protein interactions; RNA; CARRIER proteins; NERVOUS system; NEUROSCIENCES
- Publication
Journal of Neuroscience, 2009, Vol 29, Issue 16, p5153
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.0783-09.2009