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Disruption of mitochondrial complex I induces progressive parkinsonism.

TitleDisruption of mitochondrial complex I induces progressive parkinsonism.
Publication TypeJournal Article
Year of Publication2021
AuthorsGonzález-Rodríguez P, Zampese E, Stout KA, Guzman JN, Ilijic E, Yang B, Tkatch T, Stavarache MA, Wokosin DL, Gao L, Kaplitt MG, López-Barneo J, Schumacker PT, D Surmeier J
JournalNature
Date Published2021 Nov 03
ISSN1476-4687
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.

DOI10.1038/s41586-021-04059-0
Alternate JournalNature
PubMed ID34732887