Journal Article

Disruption of mitochondrial complex I induces progressive parkinsonism

Stout, Kristen A., Surmeier, D. James, Tkatch, Tatiana, Zampese, Enrico, Guzman, Jaime N., Stavarache, Mihaela A., Schumacker, Paul T., González-Rodríguez, Patricia, Kaplitt, Michael G., Wokosin, David L., López-Barneo, José, Ilijic, Ema, Gao, Lin, Yang, Ben

2021

Overview

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 . Dysfunction of mitochondrial complex I in mice is sufficient to cause progressive parkinsonism in which the loss of nigral dopamine release critically contributes to motor dysfunction.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/1 / 13/105 / 13/51 / 14 / 14/1 / 14/19 / 14/28 / 631/378/1689/1718 / 692/699/375/1718 / 9/74 / Adenosine triphosphate / Animals / Axons / Axons - drug effects / Axons - metabolism / Axons - pathology / Basal ganglia / Brain diseases / Cell Death / Central nervous system diseases / Dendrites - metabolism / Dendrites - pathology / Development and progression / Disease Models, Animal / Disease Progression / Disruption / Dopamine / Dopamine - metabolism / Dopamine receptors / Dopaminergic Neurons - drug effects / Dopaminergic Neurons - metabolism / Dopaminergic Neurons - pathology / Electron transport chain / Electron Transport Complex I - genetics / Electron Transport Complex I - metabolism / Female / Genes / Genetics / Genotype & phenotype / Humanities and Social Sciences / Levodopa / Levodopa - pharmacology / Levodopa - therapeutic use / Male / Metabolism / Mice / Mitochondria / Motor skill learning / Motor Skills - drug effects / Movement disorders / multidisciplinary / Mutation / NADH Dehydrogenase - deficiency / NADH Dehydrogenase - genetics / NADH-ubiquinone oxidoreductase / Neurodegenerative diseases / Neurological disorders / Neurons / Parkinson's disease / Parkinsonian Disorders - drug therapy / Parkinsonian Disorders - metabolism / Parkinsonian Disorders - pathology / Parkinsonian Disorders - physiopathology / Parkinsonism / Pathogenesis / Pathology / Phenotype / Phenotypes / Physiological aspects / Proteins / Science / Science (multidisciplinary) / Substantia nigra / Substantia Nigra - cytology / Substantia Nigra - drug effects / Substantia Nigra - metabolism