title: Common anti-apoptotic roles of parkin and alpha-synuclein in human dopaminergic cells.
abstract: Parkin, a product of the gene responsible for autosomal recessive juvenile parkinsonism (AR-JP), is an important player in the pathogenic process of Parkinson's disease (PD). Despite numerous studies including search for the substrate of parkin as an E3 ubiquitin-protein ligase, the mechanism by which loss-of-function of parkin induces selective dopaminergic neuronal death remains unclear. Related to this issue, 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.
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Machida
authors.forename: Tomoki
authors.initials: T
authors.lastname: Chiba
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takayanagi
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Masato
authors.initials: M
authors.lastname: Asanuma
authors.forename: Norio
authors.initials: N
authors.lastname: Ogawa
authors.forename: Akihiko
authors.initials: A
authors.lastname: Koyama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Shosuke
authors.initials: S
authors.lastname: Ito
authors.forename: Poul Hening
authors.initials: PH
authors.lastname: Jansen
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Shimizu
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004295:Dihydroxyphenylalanine / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D051843:Synucleins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein
chemical_list: D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D004295:Dihydroxyphenylalanine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D020169:Caspases; D004298:Dopamine