Disruption of mitochondrial complex I induces progressive parkinsonism
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...
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Veröffentlicht in: | Nature (London) 2021-11, Vol.599 (7886), p.650-656 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson’s disease
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. Yet, whether this change contributes to Parkinson’s disease pathogenesis is unclear
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. 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
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,
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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. |
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ISSN: | 0028-0836 1476-4687 |
DOI: | 10.1038/s41586-021-04059-0 |