TY - JOUR
T1 - Cross-seeding fibrillation of Q/N-rich proteins offers new pathomechanism of polyglutamine diseases
AU - Furukawa, Yoshiaki
AU - Kaneko, Kumi
AU - Matsumoto, Gen
AU - Kurosawa, Masaru
AU - Nukina, Nobuyuki
PY - 2009/4/22
Y1 - 2009/4/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=65549100291&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=65549100291&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0783-09.2009
DO - 10.1523/JNEUROSCI.0783-09.2009
M3 - Article
C2 - 19386911
AN - SCOPUS:65549100291
VL - 29
SP - 5153
EP - 5162
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 16
ER -