{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T22:08:29Z","timestamp":1789682909517,"version":"4.0.1"},"reference-count":60,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T00:00:00Z","timestamp":1749168000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000320","name":"Alzheimer's Society","doi-asserted-by":"publisher","award":["3242"],"award-info":[{"award-number":["3242"]}],"id":[{"id":"10.13039\/501100000320","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The age\u2010associated neurodegenerative disorder, Lewy body dementia (LBD), encompasses neuropsychiatric symptom\u2010overlapping Dementia with Lewy bodies (DLB) and Parkinson's Disease with Dementia (PDD). We characterised how differential mitochondrial DNA (mtDNA) profiles contribute to neurotype\u2010specific neurodegeneration and thereby clinicopathological heterogeneity, between LBD's syndromes. We further characterised key nuclear\u2010encoding genes' recalibrations in response to such mtDNA changes. In post\u2010mortem \u2018single\u2010cell\u2019 acetylcholine\u2010 and noradrenaline\u2010producing neurons, respectively of the pedunculopontine nucleus (PPN) and locus coeruleus (LC) from DLB, PDD and neurological\u2010control brains, we quantified \u2018major arc\u2019\u2010locating mtDNA deletions (mtDels) and \u2010copy number (mtCN), and measured mRNA levels of nuclear\u2010encoding genes regulating mtDNA maintenance, \u2010biogenesis 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\u2010noradrenergic neurons only. DLB patients' shorter survival correlated with PPN\u2010cholinergic neurons' mtDel levels, inversely with wild\u2010type mtCN, implying that such neurons' inability to maintain sufficient wild\u2010type mtDNA content drive DLBs' rapid psycho\u2010cognitive manifestations. Contrastingly, PDD's longer disease duration allowed compensation against mtDels' clonal expansion in PPN\u2010cholinergic neurons. Moreover, PDD induced mRNA depletion of a mitochondrial genome maintenance gene in PPN\u2010cholinergic neurons, whilst LC\u2010noradrenergic 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\u2010related mitochondria\u2010nuclear genetic differences question the consensus that pathology converges at disease end\u2010stage, calling for LBD subtype and neurotype\u2010specific therapeutics.<\/jats:p>","DOI":"10.1111\/acel.70125","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T04:49:37Z","timestamp":1749185377000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Type\u2010Specific Single\u2010Neuron Analysis Reveals Mitochondrial <scp>DNA<\/scp> Maintenance Failure Affecting Atrophying Pontine Neurons Differentially in Lewy Body Dementia Syndromes"],"prefix":"10.1111","volume":"24","author":[{"given":"Eloise J.","family":"Stephenson","sequence":"first","affiliation":[{"name":"Department of Neuroscience, School of Life Sciences University of Sussex  Brighton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura 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