TY - JOUR T1 - α-Synuclein-Dependent Calcium Entry Underlies Differential Sensitivity of Cultured SN and VTA Dopaminergic Neurons to a Parkinsonian Neurotoxin JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0167-17.2017 VL - 4 IS - 6 SP - ENEURO.0167-17.2017 AU - Ori J. Lieberman AU - Se Joon Choi AU - Ellen Kanter AU - Anastasia Saverchenko AU - Micah D. Frier AU - Giulia M. Fiore AU - Min Wu AU - Jyothisri Kondapalli AU - Enrico Zampese AU - D. James Surmeier AU - David Sulzer AU - Eugene V. Mosharov Y1 - 2017/11/01 UR - http://www.eneuro.org/content/4/6/ENEURO.0167-17.2017.abstract N2 - Parkinson’s disease (PD) is a debilitating neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra (SN). Although mitochondrial dysfunction and dysregulated α-synuclein (aSyn) expression are postulated to play a role in PD pathogenesis, it is still debated why neurons of the SN are targeted while neighboring dopaminergic neurons of the ventral tegmental area (VTA) are spared. Using electrochemical and imaging approaches, we investigated metabolic changes in cultured primary mouse midbrain dopaminergic neurons exposed to a parkinsonian neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). We demonstrate that the higher level of neurotoxicity in SN than VTA neurons was due to SN neuron-specific toxin-induced increase in cytosolic dopamine (DA) and Ca2+, followed by an elevation of mitochondrial Ca2+, activation of nitric oxide synthase (NOS), and mitochondrial oxidation. The increase in cytosolic Ca2+ was not caused by MPP+-induced oxidative stress, but rather depended on the activity of both L-type calcium channels and aSyn expression, suggesting that these two established pathogenic factors in PD act in concert. ER -