Phosphorylated IkappaBalpha is a component of Lewy body of Parkinson's disease.
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.
Noda
Kazuyuki
K
Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Kitami
Toshiaki
T
Gai
Wei Ping
WP
Chegini
Fariba
F
Jensen
Poul Henning
PH
Fujimura
Tsutomu
T
Murayama
Kimie
K
Tanaka
Keiji
K
Mizuno
Yoshikuni
Y
Hattori
Nobutaka
N
D045744:Cell Line, Tumor; D006801:Humans; D020672:I-kappa B Proteins / Q000032:analysis / Q000378:metabolism*; D016631:Lewy Bodies / Q000737:chemistry / Q000201:enzymology*; D000072000:NF-KappaB Inhibitor alpha; D010300:Parkinson Disease / Q000201:enzymology* / Q000473:pathology; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology; D061988:Proteasome Inhibitors; D044843:SKP Cullin F-Box Protein Ligases / Q000032:analysis; D025801:Ubiquitin / Q000032:analysis
D020672:I-kappa B Proteins; C467063:NBD peptide, mouse; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D010455:Peptides; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D000072000:NF-KappaB Inhibitor alpha; D044843:SKP Cullin F-Box Protein Ligases