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Heteroplasmic mitochondrial DNA mutations in frontotemporal lobar degeneration.

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Nie, Yu 
Murley, Alexander 
Golder, Zoe 
Rowe, James B 
Allinson, Kieren 


Frontotemporal lobar degeneration (FTLD) is a common cause of young onset dementia and is characterised by focal neuropathology. The reasons for the regional neuronal vulnerability are not known. Mitochondrial mechanisms have been implicated in the pathogenesis of FTLD, raising the possibility that frontotemporal regional mutations of mitochondrial DNA (mtDNA) are contributory causes. Here we applied dual sequencing of the entire mtDNA at high depth to identify high-fidelity single nucleotide variants (mtSNVs) and mtDNA rearrangements in post mortem brain tissue of people affected by FTLD and age-matched controls. Both mtSNVs and mtDNA rearrangements were elevated in the temporal lobe, with the greatest burden seen in FTLD. mtSNVs found in multiple brain regions also reached a higher heteroplasmy levels in the temporal lobe. The temporal lobe of people with FTLD had a higher burden of ribosomal gene variants predicted to affect intra-mitochondrial protein synthesis, and a higher proportion of missense variants in genes coding for respiratory chain subunits. In conclusion, heteroplasmic mtDNA variants predicted to affect oxidative phosphorylation are enriched in FTLD temporal lobe, and thus may contribute to the regional vulnerability in pathogenesis.



DNA, Mitochondrial, Frontotemporal Dementia, Frontotemporal Lobar Degeneration, Heteroplasmy, Humans, Mutation

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Acta Neuropathol

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Springer Science and Business Media LLC
Addenbrooke's Charitable Trust (ACT) (25/16A)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Evelyn Trust (17/08)
WBH Foundation (via Cambridge in America) (Unknown)
Wellcome Trust (212219/Z/18/Z)
Wellcome Trust (103838/Z/14/Z)
MRC (MR/S035699/1)
National Institute for Health and Care Research (IS-BRC-1215-20014)
Medical Research Council (MC_UU_00005/12)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Engineering and Physical Sciences Research Council (EP/N01426X/1)
Medical Research Council (MC_UU_00015/7)