Preserved striatal innervation and motor function despite severe loss of nigral dopamine neurons following mitochondrial dysfunction induced by mtDNA mutations
Pass, T.; Ricke, K. M.; Hofmann, P.; Chowdhury, R.; Nie, Y.; Chinnery, P. F.; Endepols, H.; Neumaier, B.; Carvalho, A.; Rigoux, L.; Steculorum, S.; Prudent, J.; Riemer, T.; Aswendt, M.; Brachvogel, B.; Wiesner, R. J.
Show abstract
Degeneration of dopamine neurons in the substantia nigra and their striatal axon terminals causes cardinal motor symptoms of Parkinsons disease (PD). In idiopathic cases, high levels of mitochondrial DNA (mtDNA) mutations associated with mitochondrial dysfunction are a central feature of these vulnerable neurons. Here we present a mouse model expressing the K320E-variant of the mitochondrial helicase Twinkle in dopamine neurons, leading to accelerated mtDNA ageing. K320E-TwinkleDaN mice showed normal motor function at 20 months of age, although already [~]70% of nigral dopamine neurons had perished. The remaining neuron population still preserved [~]75% of axon terminals in the dorsal striatum, which enabled normal dopamine release. Transcriptome analysis and viral tracing confirmed compensatory axonal sprouting of surviving nigral dopamine neurons. We conclude that a small population of substantia nigra neurons can adapt to mtDNA mutations and maintain motor control in mice, holding chances for new treatment strategies in PD patients.
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