Alpha-synuclein and mitochondrial permeability transition pore interactions in rotenone-induced Parkinson’s disease models: neuroprotective promise of cyclosporine A

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.