Alpha-synuclein and mitochondrial permeability transition pore interactions in rotenone-induced Parkinson's disease models: neuroprotective promise of cyclosporine A.
Alpha-synuclein and mitochondrial permeability transition pore interactions in rotenone-induced Parkinson's disease models: neuroprotective promise of cyclosporine A.
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Original abstract
BACKGROUND: Rotenone is widely used to develop experimental models of Parkinson's disease, but the varied toxic effects of rotenone are still not mechanistically linked to define a clear pathway of neuronal damage. METHODS: The neurotoxicity of rotenone in rats, with or without co-treatment with cyclosporine A (an inhibitor of mitochondrial permeability transition pore (mPTP) activation), has been examined in terms of neuronal death in the substantia nigra and dysfunction of isolated midbrain mitochondria. Additionally, the role of α-synuclein on rotenone-induced cell death and mitochondrial dysfunction has been explored in SH-SY5Y cells. RESULTS: In rats, nigral dopaminergic neuronal death and α-synuclein accumulation along with altered functions of midbrain mitochondria are observed after rotenone treatment; the co-treatment with cyclosporine A prevents neuronal death and all mitochondrial alterations (except complex I-III inhibition) without having a noticeable effect on α-synuclein accumulation. Likewise, in SH-SY5Y cells, exposure to rotenone for 48 h leads to cell death and mitochondrial dysfunction, which are abolished by the knockdown of α-synuclein protein expression. CONCLUSION: Together, the results suggest the pivotal role of α-synuclein in causing mitochondrial dysfunction and neural cell death presumably through mPTP activation. Further, cyclosporine A may have a potential neuroprotective effect in PD.