Publication Type Academic Article
Authors González-Rodríguez P, Zampese E, Stout K, Guzman J, Ilijic E, Yang B, Tkatch T, Stavarache M, Wokosin D, Gao L, Kaplitt M, López-Barneo J, Schumacker P, Surmeier D
Journal Nature
Volume 599
Issue 7886
Pagination 650-656
Date Published 11/03/2021
ISSN 1476-4687
Keywords Electron Transport Complex I, Parkinsonian Disorders
Abstract Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease1. Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear2. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism-which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm3,4.
DOI 10.1038/s41586-021-04059-0
PubMed ID 34732887
PubMed Central ID PMC9189968
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