Parkin cleaves intracellular alpha-synuclein inclusions via the activation of calpain.
Mutations in the alpha-synuclein and parkin genes cause heritable forms of Parkinson's disease. In the present study, we examined the possible functional relationship between the parkin and alpha-synuclein genes in a conditionally immortalized embryonic hippocampal cell (H19-7) line. Whereas transient transfection of alpha-synuclein into neuronal H19-7 cells caused the formation of its intracytoplasmic inclusions and a significant cell death, the combined overexpression of parkin restored the alpha-synuclein-induced decrease in cell viability to control levels. In addition, the overexpression of parkin was found to generate selective cleavage of alpha-synuclein. Furthermore, the cytoprotective effect of parkin on alpha-synuclein-induced cell death was not inhibited in the presence of a proteasome inhibitor. Interestingly, the overexpression of parkin induced the activation of an intracellular cysteine protease, calpain, but not caspase, and the cytoprotective effect of parkin on alpha-synuclein cytotoxicity was significantly inhibited by the presence of calpain-specific inhibitors. In conclusion, our results suggest that parkin accelerates the degradation of alpha-synuclein via the activation of the nonproteasomal protease, calpain, leading to the prevention of alpha-synuclein-induced cell death in embryonic hippocampal progenitor cells.
Kim
Se Jung
SJ
Department of Biology, Yonsei University College of Sciences, Shinchon-dong 134, Seodaemun-gu, Seoul 120-749, Korea.
Sung
Jee Young
JY
Um
Ji Won
JW
Hattori
Nobutaka
N
Mizuno
Yoshikuni
Y
Tanaka
Keiji
K
Paik
Seung R
SR
Kim
Jongsun
J
Chung
Kwang Chul
KC
D000818:Animals; D002154:Calpain / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004336:Drug Antagonism; D004789:Enzyme Activation; D002479:Inclusion Bodies; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D051843:Synucleins; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D002154:Calpain