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Neurobiol Aging. 2015 Sep;36(9):2617-27. doi: 10.1016/j.neurobiolaging.2015.05.008. Epub 2015 May 16.

Genetic reduction of mitochondrial complex I function does not lead to loss of dopamine neurons in vivo.

Author information

1
Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; College of Life Sciences, Sejong University, Seoul, Korea.
2
Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; School of Biological Sciences and Technology, College of Natural Sciences, Chonnam National University, Gwangju, Korea; College of Medicine, Chonnam National University, Gwangju, Korea.
3
Graduate Program in Neurobiology & Behavior, University of Washington, Seattle, WA, USA.
4
School of Biological Sciences and Technology, College of Natural Sciences, Chonnam National University, Gwangju, Korea; College of Medicine, Chonnam National University, Gwangju, Korea.
5
Sorbonne Universités, Université Pierre et Marie Curie, UMR_CR18, Neuroscience Paris-Seine, Paris, France; Centre National de la Recherche Scientifique UMR 8246, Paris, France; Institut National de la Santé et de la Rechesrche Médicale U1130, Paris, France.
6
Howard Huges Medical Institute, University of Washington, Seattle, WA, USA; Department of Biochemistry, University of Washington, Seattle, WA, USA.
7
Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; Graduate Program in Neurobiology & Behavior, University of Washington, Seattle, WA, USA. Electronic address: zxia@uw.edu.

Abstract

Inhibition of mitochondrial complex I activity is hypothesized to be one of the major mechanisms responsible for dopaminergic neuron death in Parkinson's disease. However, loss of complex I activity by systemic deletion of the Ndufs4 gene, one of the subunits comprising complex I, does not cause dopaminergic neuron death in culture. Here, we generated mice with conditional Ndufs4 knockout in dopaminergic neurons (Ndufs4 conditional knockout mice [cKO]) to examine the effect of complex I inhibition on dopaminergic neuron function and survival during aging and on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in vivo. Ndufs4 cKO mice did not show enhanced dopaminergic neuron loss in the substantia nigra pars compacta or dopamine-dependent motor deficits over the 24-month life span. These mice were just as susceptible to MPTP as control mice. However, compared with control mice, Ndufs4 cKO mice exhibited an age-dependent reduction of dopamine in the striatum and increased α-synuclein phosphorylation in dopaminergic neurons of the substantia nigra pars compacta. We also used an inducible Ndufs4 knockout mouse strain (Ndufs4 inducible knockout) in which Ndufs4 is conditionally deleted in all cells in adult to examine the effect of adult onset, complex I inhibition on MPTP sensitivity of dopaminergic neurons. The Ndufs4 inducible knockout mice exhibited similar sensitivity to MPTP as control littermates. These data suggest that mitochondrial complex I inhibition in dopaminergic neurons does contribute to dopamine loss and the development of α-synuclein pathology. However, it is not sufficient to cause cell-autonomous dopaminergic neuron death during the normal life span of mice. Furthermore, mitochondrial complex I inhibition does not underlie MPTP toxicity in vivo in either cell autonomous or nonautonomous manner. These results provide strong evidence that inhibition of mitochondrial complex I activity is not sufficient to cause dopaminergic neuron death during aging nor does it contribute to dopamine neuron toxicity in the MPTP model of Parkinson's disease. These findings suggest the existence of alternative mechanisms of dopaminergic neuron death independent of mitochondrial complex I inhibition.

KEYWORDS:

Dopamine neuron; Mitochondrial complex I; Parkinson's disease

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