Phosphorylated IkappaBalpha is a component of Lewy body of Parkinson's disease |
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Authors: | Noda Kazuyuki Kitami Toshiaki Gai Wei Ping Chegini Fariba Jensen Poul Henning Fujimura Tsutomu Murayama Kimie Tanaka Keiji Mizuno Yoshikuni Hattori Nobutaka |
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Affiliation: | Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. |
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Abstract: | Ubiquitin is one of the major components of Lewy bodies (LB), the pathological hallmark of Parkinson's disease (PD). Here, we identified that a phosphorylated form of IkappaBalpha (pIkappaBalpha), an inhibitor of NF-kappaB, and SCF(beta-TrCP), the ubiquitin ligase of pIkappaBalpha, are components of LB in brains of PD patients. In vitro studies identified those proteins in the ubiquitin- and alpha-synuclein (known as the major component of LB)-positive LB-like inclusions generated in dopaminergic SH-SY5Y cells treated with MG132, a proteasome inhibitor. Intriguingly, IkappaBalpha migration into such ubiquitinated inclusions in cells treated with MG132 was inhibited by a cell-permeable peptide known to block phosphorylation of IkappaBalpha, although this peptide did not influence cell viability under proteasomal inhibition. Our results indicate that phosphorylation of IkappaBalpha plays a role in the formation of IkappaBalpha-containing inclusions caused by proteasomal dysfunction, and that the generation of such inclusion is independent of cell death caused by impairment of proteasome. |
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Keywords: | Parkinson’s disease Lewy bodies Ubiquitin Proteasome IκBα IκB-kinase |
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