This study has shown that purified recombinant human α-synuclein (20 μM) 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 (5 
μM), a proteasomal inhibitor, causes an accumulation of α-synuclein with 
concomitant mitochondrial dysfunction and cell death. The effects of lactacystin 
on intact SHSY5Y cells are, however, prevented by knocking down α-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 (1 μM) which blocks the activity of the 
mitochondrial permeability transition pore. Likewise, in wild-type SHSY5Y cells, 
typical mitochondrial poison like antimycin A (50 nM) produces loss of cell 
viability comparable to that of lactacystin (5 μM). These data, in combination 
with those from isolated brain mitochondria, strongly suggest that 
intracellularly accumulated α-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. α-Synuclein is shown to cause 
mitochondrial impairment through interaction with permeability transition pore 
complex in isolated preparations. Intracellular accumulation of α-synuclein in 
SHSY5Y cells following proteasomal inhibition leads to mitochondrial impairment 
and cell death which could be prevented by knocking down α-synuclein gene. The 
results link mitochondrial dysfunction and α-synuclein accumulation, two key 
pathogenic mechanisms of Parkinson's disease, in a common damage pathway.