[Pathogenesis of Parkinson's disease: a common pathway between alpha-synuclein and parkin and the mechanism of Lewy bodies formation].
Parkin, a product of Park2 gene, is an important player in the pathogenic process of Parkinson's disease (PD). Despite numerous studies including search for the substrate of parkin, the mechanism by which loss-of-function of parkin induces selective dopaminergic neuronal death remains unclear. Here we show that antisense knockdown of parkin causes apoptotic cell death of human dopaminergic SH-SY5Y cells associated with caspase activation and accompanied by accumulation of oxidative dopamine (DA) metabolites due to auto-oxidation of DOPA and DA. Forced expression of alpha-synuclein (alpha-SN), another familial PD gene product, prevented accumulation of oxidative DOPA/DA metabolites and cell death caused by parkin loss. Our findings indicate that both parkin and alpha-SN share a common pathway in DA metabolism whose abnormality leads to accumulation of oxidative DA metabolites and subsequent cell death. In addition, we identified a phosphorylated form of IkappaBalpha (pIkappaBalpha), an inhibitor of the NF-kappaB signaling pathway, and the components of the SCF(beta-TrCP), ubiquitin ligase of pIkappaBalpha, are novel protein components in LBs. Subsequently, we showed those proteins are included in the ubiquitin-LB-like inclusions generated by treatment of a proteasome inhibitor. Furthermore, the generation of the inclusions are independent on cell death due to impairment of the proteasome.
Hattori
Nobutaka
N
Department of Neurology, Juntendo University School of Medicine.
Machida
Yutaka
Y
Noda
Kazuyuki
K
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D016631:Lewy Bodies / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D010300:Parkinson Disease / Q000209:etiology* / Q000378:metabolism; D010766:Phosphorylation; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D051844:alpha-Synuclein; D000072000:NF-KappaB Inhibitor alpha; C104705:dopamine quinone; D004295:Dihydroxyphenylalanine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine