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- CLINICA NEUROL, 45: 905－907, 2005
- Vol.45 No.11 contents
The 46th Annual Meeting of the Japanese Society of Neurology
Pathogenesis of Parkinson's disease: a common pathway between α-synuclein and parkin and the mechanism of Lewy bodies formation
Nobutaka Hattori, M.D., Yutaka Machida, M.D. and Kazuyuki Noda, M.D.
Department of Neurology, Juntendo University School of Medicine
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 a-synuclein (α-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 α-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 IkBα (pIkBα), an inhibitor of the NF-kB signaling pathway, and the components of the SCFβ-TrCP), ubiquitin ligase of pIkBα, 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.
(CLINICA NEUROL, 45: 905－907, 2005)
key words: parkin, α-synuclein, dopa·dopamin quinone, phosphorylation, IkappB
(Received: 26-May-05)
