Type‐specific single‐neuron analysis reveals mitochondrial DNA maintenance failure affecting atrophying pontine neurons differentially in Lewy body dementia syndromes

The age‐associated neurodegenerative disorder, Lewy body dementia (LBD), encompasses neuropsychiatric symptom‐overlapping Dementia with Lewy bodies (DLB) and Parkinson's Disease with Dementia (PDD). We characterised how differential mitochondrial DNA (mtDNA) profiles contribute to neurotype‐specific neurodegeneration and thereby clinicopathological heterogeneity, between LBD's syndromes. We further characterised key nuclear‐encoding genes' recalibrations in response to such mtDNA changes. In post‐mortem ‘single‐cell’ acetylcholine‐ and noradrenaline‐producing neurons, respectively of the pedunculopontine nucleus (PPN) and locus coeruleus (LC) from DLB, PDD and neurological‐control brains, we quantified ‘major arc’‐locating mtDNA deletions (mtDels) and ‐copy number (mtCN), and measured mRNA levels of nuclear‐encoding genes regulating mtDNA maintenance, ‐biogenesis and mitophagy. DLB cases' OXPHOS defect instigating mtDel burden was higher in both neurotypes than PDD. In DLB, mtCN was reduced for both neurotypes, but PDD cases revealed mtDNA depletion in LC‐noradrenergic neurons only. DLB patients' shorter survival correlated with PPN‐cholinergic neurons' mtDel levels, inversely with wild‐type mtCN, implying that such neurons' inability to maintain sufficient wild‐type mtDNA content drive DLBs' rapid psycho‐cognitive manifestations. Contrastingly, PDD's longer disease duration allowed compensation against mtDels' clonal expansion in PPN‐cholinergic neurons. Moreover, PDD induced mRNA depletion of a mitochondrial genome maintenance gene in PPN‐cholinergic neurons, whilst LC‐noradrenergic neurons displayed reduced expression of a mitophagy regulating gene. Here we identify mitochondrial genome maintenance and mitophagy pathway enrichment as therapeutic targets to offset defective mtDNA within pontine cholinergic and noradrenergic neurons of PDD patients. The pronounced LBD subtype‐related mitochondria‐nuclear genetic differences question the consensus that pathology converges at disease end‐stage, calling for LBD subtype and neurotype‐specific therapeutics.