TRPC1 inhibits apoptotic cell degeneration induced by dopaminergic neurotoxin MPTP/MPP(+).
Disturbances in Ca(2+) homeostasis have been implicated in a variety of neuropathological conditions including Parkinson's disease (PD). However, the importance of store-operated Ca(2+) entry (SOCE) channels in PD remains to be investigated. In the present study, we have scrutinized the significance of TRPC1 in 1-methyl-4-phenyl-1,2,3,6-tetrahyrdro-pyridine (MPTP)-induced PD using C57BL/6 animal model and PC12 cell culture model. Both sub-acute and sub-chronic treatments of MPTP significantly reduced TRPC1, and tyrosine hydroxylase levels, but not TRPC3, along with increased neuronal death. Furthermore, MPTP induces mitochondrial dysfunction, which was associated with reduced mitochondrial membrane potential, decreased level of Bcl(2), Bcl-xl, and an altered Bcl-xl/Bax ratio thereby initiating apoptosis. Importantly, TRPC1 overexpression in PC12 cells showed significant protection against MPP(+) induced neuronal apoptosis, which was attributed to the restoration of cytosolic Ca(2+) and preventing loss of mitochondrial membrane potential. Silencing of TRPC1 or addition of TRPC1 channel blockers decreased mitochondrial membrane potential, whereas activation of TRPC1 restored mitochondrial membrane potential in cells overexpressing TRPC1. TRPC1 overexpression also inhibited Bax translocation to the mitochondria and thereby prevented cytochrome c release and mitochondrial-mediated apoptosis. Overall, these results provide compelling evidence for the role of TRPC1 in either onset/progression of PD and restoration of TRPC1 levels could limit neuronal degeneration in MPTP mediated PD.
Selvaraj
Senthil
S
Department of Biochemistry & Molecular Biology, University of North Dakota, Grand Forks, 58201, United States.
Watt
John A
JA
Singh
Brij B
BB
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D015259:Dopamine Agents / Q000633:toxicity*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D050052:TRPC Cation Channels / Q000378:metabolism*
D015259:Dopamine Agents; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D002118:Calcium
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