Selective inhibition of mitochondrial sodium-calcium exchanger protects striatal neurons from α-synuclein plus rotenone induced toxicity.

Progressive accumulation of α-synuclein (α-syn) and exposure to environmental toxins are risk factors that may both concur to Parkinson's disease (PD) pathogenesis. Electrophysiological recordings of field postsynaptic potentials (fEPSPs) and Ca measures in striatal brain slices and differentiated SH-SY5Y cells showed that co-application of α-syn and the neurotoxic pesticide rotenone (Rot) induced Ca dysregulation and alteration of both synaptic transmission and cell function. Interestingly, the presence of the mitochondrial NCX inhibitor CGP-37157 prevented these alterations. The specific involvement of the mitochondrial NCX was confirmed by the inability of the plasma membrane inhibitor SN-6 to counteract such phenomenon. Of note, using a siRNA approach, we found that NCX1 was the isoform specifically involved. These findings suggested that NCX1, operating on the mitochondrial membrane, may have a critical role in the maintenance of ionic Ca homeostasis in PD and that its inhibition most likely exerts a protective effect in the toxicity induced by α-syn and Rot.