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eNeuro. 2017 Nov 21;4(6). pii: ENEURO.0167-17.2017. doi: 10.1523/ENEURO.0167-17.2017. eCollection 2017 Nov-Dec.

α-Synuclein-Dependent Calcium Entry Underlies Differential Sensitivity of Cultured SN and VTA Dopaminergic Neurons to a Parkinsonian Neurotoxin.

Author information

1
New York State Psychiatric Institute, Columbia University Medical Center, New York, NY 10032.
2
Department of Psychiatry, Columbia University Medical Center, New York, NY 10032.
3
Department of Neurology, Columbia University Medical Center, New York, NY 10032.
4
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
5
Department of Pharmacology, Columbia University Medical Center, New York, NY 10032.

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.

KEYWORDS:

MPP+; MPTP; Parkinson’s disease; calcium; dopamine; mitochondria; neurodegeneration; α-synuclein

PMID:
29177188
PMCID:
PMC5701296
DOI:
10.1523/ENEURO.0167-17.2017
[Indexed for MEDLINE]
Free PMC Article

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