α-synuclein-dependent calcium entry underlies differential sensitivity of cultured SN and VTA dopaminergic neurons to a parkinsonian neurotoxin

Ori J. Lieberman, Se Joon Choi, Ellen Kanter, Anastasia Saverchenko, Micah D. Frier, Giulia M. Fiore, Min Wu, Jyothisri Kondapalli, Enrico Zampese, D. James Surmeier, David Sulzer, Eugene V. Mosharov*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere0167-17.2017
JournaleNeuro
Volume4
Issue number6
DOIs
StatePublished - Nov 1 2017

Keywords

  • Calcium
  • Dopamine
  • MPP
  • MPTP
  • Mitochondria
  • Neurodegeneration
  • Parkinson’s disease
  • α-synuclein

ASJC Scopus subject areas

  • Neuroscience(all)

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