Proceedings of The Physiological Society
King's College London (2011) Proc Physiol Soc 22, PC24
Mitochondrial dysfunction causes age-related and cell type-specific neurodegeneration
D. M. Humphrey1, F. Hirth1
1. Department of Neuroscience, King's College London, London, United Kingdom.
Mitochondrial dysfunction has been associated with several major neurodegenerative disorders, including Parkinson’s disease (PD). Among the pathological changes observed in PD is the progressive loss of dopaminergic (DA) neurons in the Substantia Nigra of the ventral midbrain. Ageing individuals with PD have high levels of mitochondrial DNA (mtDNA) alterations, and mutations in PD-related genes PINK1 and parkin have been associated with reduced mtDNA copy numbers and decreased mitochondrial respiratory activity. However, it is not clear whether mtDNA alterations and mitochondrial dysfunction are causally related to DA neurodegeneration. In order to address this question in vivo, we knocked down the sole mitochondrial DNA polymerase, POLGα, in a cell-type specific manner in Drosophila. POLGα knockdown dramatically decreased the level of mtDNA. POLGα-related mitochondrial dysfunction in dopaminergic, but not in cholinergic or in serotonergic neurons, resulted in adult-onset, age-related motor deficits and DA-specific neurodegeneration. Lethality caused by POLGα knockdown could be rescued, at least to some extent, by targeted genetic manipulation of either PINK1/parkin signalling or by Drp1, both of which have been implicated in mitochondrial dynamics. Full rescue of lethality was achieved by genetically bypassing respiratory deficiencies affecting complexes 1, 3 and 4. In addition, enhancement of the electron transport chain by nicotinamide, ameliorated locomotor defects and prevented DA neuron loss. Our results demonstrate that mtDNA alterations lead to respiratory chain deficiencies that cause age-related DA neurodegeneration underlying PD.
Where applicable, experiments conform with Society ethical requirements