Journal
JOURNAL OF NEUROCHEMISTRY
Volume 131, Issue 6, Pages 868-877Publisher
WILEY
DOI: 10.1111/jnc.12966
Keywords
Parkinson's disease; -synuclein; lactacystin; mitochondrial dysfunction; permeability transition pore; cyclophilin D
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Funding
- Department of Science and Technology, Government of India [SR/SO/HS 0026/2012]
- National Health and Medical Research Council of Australia (NHMRC)
- Department of Biotechnology, Government of India
- West Bengal university of Health Sciences
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This study has shown that purified recombinant human -synuclein (20M) causes membrane depolarization and loss of phosphorylation capacity of isolated purified rat brain mitochondria by activating permeability transition pore complex. In intact SHSY5Y (human neuroblastoma cell line) cells, lactacystin (5M), a proteasomal inhibitor, causes an accumulation of -synuclein with concomitant mitochondrial dysfunction and cell death. The effects of lactacystin on intact SHSY5Y cells are, however, prevented by knocking down -synuclein expression by specific siRNA. Furthermore, in wild-type (non-transfected) SHSY5Y cells, the effects of lactacystin on mitochondrial function and cell viability are also prevented by cyclosporin A (1M) which blocks the activity of the mitochondrial permeability transition pore. Likewise, in wild-type SHSY5Y cells, typical mitochondrial poison like antimycin A (50nM) produces loss of cell viability comparable to that of lactacystin (5M). These data, in combination with those from isolated brain mitochondria, strongly suggest that intracellularly accumulated -synuclein can interact with mitochondria in intact SHSY5Y cells causing dysfunction of the organelle which drives the cell death under our experimental conditions. The results have clear implications in the pathogenesis of sporadic Parkinson's disease.
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