An investigation of critical pathways for mitochondrial DNA maintenance in brainstem nuclei in Lewy Body Dementia clinical subtypes.

Lewy Body Dementia (LBD) encompasses both Dementia with Lewy Bodies (DLB) and Parkinson’s Disease with Dementia (PDD), distinguished via the 'one year rule' between onset of dementia and parkinsonism. Consensus exists that phenotypes converge end stage, suggesting similar pathological mechanisms i.e. type-specific neuronal loss and protein aggregates in remaining neurons. Deletions in mitochondrial DNA (mtDNA), encoding OXPHOS components, may underlie the neurodegeneration, as previously showed for Parkinson’s disease. We quantified mtDNA deletion (mtDel) levels and mtDNA copy number (mtCN) in single acetylcholine (ACh)- and noradrenaline- (NA) producing neurons from two degenerating pontine nuclei, the pedunculopontine nucleus (PPN) and locus coeruleus (LC) in post-mortem DLB, PDD and neurologically normal control brains. Regarding the DLB cohort, both PPN ACh and LC NA neurons harboured a significantly greater mtDel burden. Whilst LC NA neurons also showed a significant decrease in mtCN in this disease cohort, PPN Ach neurons did not. PDD neurons showed contrasting mtDel loads between the LC NA and PPN ACh neurons - the former containing significantly lower mtDel levels and the latter containing significantly higher levels of mtDels. To investigate potential mechanistic explanations for these results, we quantified mRNA expression of nuclear encoded genes regulating mtDNA repair (TFAM), biogenesis (PGC1α) and mitophagy (PINK1). Expression analysis of TFAM, PGC1α and PINK1 revealed a decreased expression of TFAM in the PDD cohort of PPN ACh neurons, as well as a decreased expression of PINK1 in the PDD cohort of LC NA neurons. Our results indicate that LBD-affected brainstem neurons fail to maintain sufficient copies of wild-type mtDNA, the degree of pathological burden being neurotype and clinical subtype dependent.