Heteroplasmic mitochondrial DNA mutations in frontotemporal lobar degeneration.
Publication Date
2022-06Journal Title
Acta Neuropathol
ISSN
0001-6322
Publisher
Springer
Volume
143
Issue
6
Pages
687-695
Language
en
Type
Article
This Version
VoR
Metadata
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Nie, Y., Murley, A., Golder, Z., Rowe, J. B., Allinson, K., & Chinnery, P. (2022). Heteroplasmic mitochondrial DNA mutations in frontotemporal lobar degeneration.. Acta Neuropathol, 143 (6), 687-695. https://doi.org/10.1007/s00401-022-02423-6
Abstract
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.
Keywords
Original Paper
Sponsorship
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 Research (NIHRDH-IS-BRC-1215-20014)
Identifiers
s00401-022-02423-6, 2423
External DOI: https://doi.org/10.1007/s00401-022-02423-6
This record's URL: https://www.repository.cam.ac.uk/handle/1810/337165
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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