Conditional deletion of Ndufs4 in dopaminergic neurons promotes Parkinson's disease-like non-motor symptoms without loss of dopamine neurons.
Reduction of mitochondrial complex I activity is one of the major hypotheses for dopaminergic neuron death in Parkinson's disease. However, reduction of complex I activity in all cells or selectively in dopaminergic neurons via conditional deletion of the Ndufs4 gene, a subunit of the mitochondrial complex I, does not cause dopaminergic neuron death or motor impairment. Here, we investigated the effect of reduced complex I activity on non-motor symptoms associated with Parkinson's disease using conditional knockout (cKO) mice in which Ndufs4 was selectively deleted in dopaminergic neurons (Ndufs4 cKO). This conditional deletion of Ndufs4, which reduces complex I activity in dopamine neurons, did not cause a significant loss of dopaminergic neurons in substantia nigra pars compacta (SNpc), and there was no loss of dopaminergic neurites in striatum or amygdala. However, Ndufs4 cKO mice had a reduced amount of dopamine in the brain compared to control mice. Furthermore, even though motor behavior were not affected, Ndufs4 cKO mice showed non-motor symptoms experienced by many Parkinson's disease patients including impaired cognitive function and increased anxiety-like behavior. These data suggest that mitochondrial complex I dysfunction in dopaminergic neurons promotes non-motor symptoms of Parkinson's disease and reduces dopamine content in the absence of dopamine neuron loss.
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.|School of Biological Sciences and Technology, College of Natural Sciences, College of Medicine, Chonnam National University, Gwangju 61186, Korea.
Won-Seok
WS
Choi
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.|College of Life Sciences, Sejong University, Seoul 05006, Korea.
Hyung-Wook
HW
Kim
Sorbonne Universités, Université Pierre et Marie Curie, UMR_CR18, Neuroscience, Paris-Seine, F-75005, Paris.
François
F
Tronche
Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Richard D
RD
Palmiter
Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
Daniel R
DR
Storm
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
Zhengui
Z
Xia
D000818:Animals; D001007:Anxiety / Q000235:genetics; D001522:Behavior, Animal; D016923:Cell Death; D060825:Cognitive Dysfunction; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000235:genetics*; D017353:Gene Deletion; D008297:Male; D018782:Maze Learning; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D012701:Serotonin / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C534449:Ndufs4 protein, mouse; D012701:Serotonin; D014446:Tyrosine 3-Monooxygenase; D042967:Electron Transport Complex I; D004298:Dopamine