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.