Mitochondrial DNA changes in pedunculopontine cholinergic neurons in Parkinson disease

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Parkinson disease (PD) patients typically present with tremor, bradykinesia, and rigidity, the onset and progression of which associate with selective loss of nigrostriatal dopaminergic neurons.1 Interest has grown as to the role of nondopaminergic neurotransmission in PD. Cholinergic degeneration, affecting the basal forebrain, the nucleus basalis of Meynert, and a rostral brainstem structure called the pedunculopontine nucleus (PPN), associates with the onset and development of “axial” signs and cognitive impairment seen in PD patients.2 Surviving (but susceptible) cholinergic neurons in these nuclei contain aggregated α‐synuclein fibrils, forming Lewy bodies and Lewy neurites, a neuropathological hallmark of PD.3
The links between mitochondria and PD pathoetiology are well studied.5 This commenced in the 1980s, when the potent respiratory chain inhibitor 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine, serving as a prodrug to the neurotoxin MPP+, was shown to cause parkinsonism in illicit drug users,6 through to identification of complex‐I–mediated reactive oxygen species forming within PD brains,7 and continuing with inherited and somatic mitochondrial DNA (mtDNA) variants that were shown to affect PD risk.8 Additionally, changes in mitochondrial DNA copy number (mtCN) were shown to associate with PD pathology, with vulnerable dopaminergic neurons showing depleted levels of wild‐type mtCN.11
Recently, we showed that several mitochondrial respiratory chain proteins are significantly upregulated in γ‐aminobutyric acidergic and glycinergic PPN neurons from PD postmortem brains.3 Conversely, in the same patients, there was a marked reduction of these mitochondrial proteins in the cholinergic neurons of the PPN, suggesting mitochondrial injury. Moreover, we observed a significant reduction in mitochondrial mass across all 3 neuronal types, with the most pronounced loss seen in PPN cholinergic neurons.3 Given the links between PPN cholinergic neuronal deterioration, mitochondrial function, and the development of PD, we investigated the role of mtDNA maintenance and stability in cholinergic neurons from the PPN of PD patients and controls.

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