Disruption of mitochondrial complex I induces progressive parkinsonism.

Autor: González-Rodríguez P; Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., Zampese E; Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., Stout KA; Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., Guzman JN; Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., Ilijic E; Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., Yang B; Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., Tkatch T; Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., Stavarache MA; Department of Neurological Surgery, Weill Cornell Medical College, New York, NY, USA., Wokosin DL; Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., Gao L; Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla and CIBERNED, Seville, Spain., Kaplitt MG; Department of Neurological Surgery, Weill Cornell Medical College, New York, NY, USA., López-Barneo J; Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla and CIBERNED, Seville, Spain., Schumacker PT; Department of Pediatrics, Northwestern University, Chicago, IL, USA., Surmeier DJ; Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. j-surmeier@northwestern.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 Nov; Vol. 599 (7886), pp. 650-656. Date of Electronic Publication: 2021 Nov 03.
DOI: 10.1038/s41586-021-04059-0
Abstrakt: Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease 1 . Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear 2 . 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 paradigm 3,4 .
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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