Common anti-apoptotic roles of parkin and alpha-synuclein in human dopaminergic cells.
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.
Machida
Yutaka
Y
Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
Chiba
Tomoki
T
Takayanagi
Atsushi
A
Tanaka
Yoshikazu
Y
Asanuma
Masato
M
Ogawa
Norio
N
Koyama
Akihiko
A
Iwatsubo
Takeshi
T
Ito
Shosuke
S
Jansen
Poul Hening
PH
Shimizu
Nobuyoshi
N
Tanaka
Keiji
K
Mizuno
Yoshikuni
Y
Hattori
Nobutaka
N
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
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