Abstract
The selective degeneration of dopaminergic (DA) midbrain neurons in the substantia nigra (SN) is a hallmark of Parkinson disease. DA neurons in the neighboring ventral tegmental area (VTA) are significantly less affected. The mechanisms for this differential vulnerability of DA neurons are unknown. We identified selective activation of ATP-sensitive potassium (K-ATP) channels as a potential mechanism. We show that in response to parkinsonism-inducing toxins, electrophysiological activity of SN DA neurons, but not VTA DA neurons, is lost owing to activation of K-ATP channels. This selective K-ATP channel activation is controlled by differences in mitochondrial uncoupling between SN and VTA DA neurons. Genetic inactivation of the K-ATP channel pore-forming subunit Kir6.2 resulted in a selective rescue of SN but not VTA DA neurons in two mechanistically distinct mouse models of dopaminergic degeneration, the neurotoxicological 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model and the mutant weaver mouse. Thus, K-ATP channel activation has an unexpected role in promoting death of DA neurons in chronic disease.
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Acknowledgements
We are grateful to F.M. Ashcroft and R. Veh for support. We thank the animal facility of Marburg University for animal care and J. Clark, D. Meyer, E. Naudascher and H. Neuhoff for technical support. This work was supported by the Parkinson's Disease Society, UK, the Medical Research Council, Bundesministerium fuer Bildung und Forschung (BMBF-NGFNII), Gemeinnützige Hertie Foundation, Royal Society, Deutsche Forschungsgemeinschaft (J.W.), and fellowships from New College, Oxford and the Royal Society (B.L.) and Exeter College, Oxford (J.R.).
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Liss, B., Haeckel, O., Wildmann, J. et al. K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons. Nat Neurosci 8, 1742–1751 (2005). https://doi.org/10.1038/nn1570
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DOI: https://doi.org/10.1038/nn1570
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