BimEL up-regulation potentiates AIF translocation and cell death in response to MPTP.
This study attempted to elucidate the signaling mechanism underlying dopaminergic cell death in the MPP+ model for Parkinson's disease. In neuronal-differentiated PC12 cells, through the regulation by activated JNK and c-jun, BimEL expression was markedly increased in response to MPP+ treatment, which led to the cell degeneration. In lieu of Smac translocation as seen in other paradigms, up-regulation of BimEL effected an increase in calpain I activity that, in turn, mediated AIF release from the mitochondria. In support, we found that knocking down BimEL expression resulted in a decrease in calpain I activity, as well as AIF release from the mitochondria and cell death. Finally, inhibition of calpain activity mitigated AIF release from the mitochondria and cell death. Under cell-free conditions, activated purified calpain I could induce the release of AIF from isolated mitochondria without the participation of BimEL or activated JNK, suggesting that AIF release is a direct consequence of calpain I activity. In concert, the results suggest a novel signaling pathway for dopaminergic cell degeneration, in which MPP+ induces the up-regulation of BimEL, which in turn potentiates an elevation in calpain I activity that mediates AIF release and cell death in a caspase-independent manner.
Liou
Anthony K F
AK
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. lioukf@upmc.edu
Zhou
Zhigang
Z
Pei
Wei
W
Lim
Tit-Meng
TM
Yin
Xiao-Ming
XM
Chen
Jun
J
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000502:physiology; D016923:Cell Death / Q000187:drug effects*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology*; D016716:PC12 Cells; D021381:Protein Transport / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051381:Rats; D015854:Up-Regulation
D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D002154:Calpain; D015655:1-Methyl-4-phenylpyridinium; D002118:Calcium