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Altered dopamine metabolism and increased vulnerability to MPTP in mice with partial deficiency of mitochondrial complex I in dopamine neurons.

MPG-Autoren

Sterky,  Fredrik H
Max Planck Society;

Hoffman,  Alexander F
Max Planck Society;

Milenkovic,  Dusanka
Max Planck Society;

Bao,  Betty
Max Planck Society;

Paganelli,  Arianna
Max Planck Society;

Edgar,  Daniel
Max Planck Society;

Wibom,  Rolf
Max Planck Society;

Lupica,  Carl R
Max Planck Society;

Olson,  Lars
Max Planck Society;

Larsson,  Nils-Göran
Max Planck Society;

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Zitation

Sterky, F. H., Hoffman, A. F., Milenkovic, D., Bao, B., Paganelli, A., Edgar, D., et al. (2012). Altered dopamine metabolism and increased vulnerability to MPTP in mice with partial deficiency of mitochondrial complex I in dopamine neurons. Hum Mol Genet, 21(5), 1078-1089.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0028-59C3-D
Zusammenfassung
A variety of observations support the hypothesis that deficiency of complex I [reduced nicotinamide-adenine dinucleotide (NADH):ubiquinone oxidoreductase] of the mitochondrial respiratory chain plays a role in the pathophysiology of Parkinson's disease (PD). However, recent data from a study using mice with knockout of the complex I subunit NADH:ubiquinone oxidoreductase iron-sulfur protein 4 (Ndufs4) has challenged this concept as these mice show degeneration of non-dopamine neurons. In addition, primary dopamine (DA) neurons derived from such mice, reported to lack complex I activity, remain sensitive to toxins believed to act through inhibition of complex I. We tissue-specifically disrupted the Ndufs4 gene in mouse heart and found an apparent severe deficiency of complex I activity in disrupted mitochondria, whereas oxidation of substrates that result in entry of electrons at the level of complex I was only mildly reduced in intact isolated heart mitochondria. Further analyses of detergent-solubilized mitochondria showed the mutant complex I to be unstable but capable of forming supercomplexes with complex I enzyme activity. The loss of Ndufs4 thus causes only a mild complex I deficiency in vivo. We proceeded to disrupt Ndufs4 in midbrain DA neurons and found no overt neurodegeneration, no loss of striatal innervation and no symptoms of Parkinsonism in tissue-specific knockout animals. However, DA homeostasis was abnormal with impaired DA release and increased levels of DA metabolites. Furthermore, Ndufs4 DA neuron knockouts were more vulnerable to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Taken together, these findings lend in vivo support to the hypothesis that complex I deficiency can contribute to the pathophysiology of PD.