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

• Published in: Cell death & disease 2019-01, Vol.10 (2), p.80, Article 80
• Main Authors: Bastioli, Guendalina, Piccirillo, Silvia, Castaldo, Pasqualina, Magi, Simona, Tozzi, Alessandro, Amoroso, Salvatore, Calabresi, Paolo
• Format: Article
• Language: English
• Subjects: 13; 14; 14/19; 42/89; 631/378/87; 692/699/375/1718; 9/30; alpha-Synuclein - adverse effects; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Brain slice preparation; Calcium (mitochondrial); Calcium homeostasis; Cell Biology; Cell Culture; Corpus Striatum - metabolism; Disease Models, Animal; Homeostasis; Humans; Immunology; Life Sciences; Mitochondria; Mitochondria - metabolism; Movement disorders; Na+/Ca2+ exchanger; NCX1 protein; Neostriatum; Neurodegenerative diseases; Neurons - metabolism; Neurotoxicity; Parkinson Disease; Parkinson's disease; Rats; Rats, Wistar; Risk factors; Rot; Rotenone; Rotenone - adverse effects; siRNA; Sodium; Sodium-Calcium Exchanger - metabolism; Synaptic transmission; Synuclein
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-1290-6

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 2+ 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 2+ 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 2+ homeostasis in PD and that its inhibition most likely exerts a protective effect in the toxicity induced by α-syn and Rot.