Journal article
The T9861C Mutation in the mtDNA-Encoded Cytochrome C Oxidase Subunit III Gene Occurs in High Frequency but with Unequal Distribution in the Alzheimer's Disease Brain
Journal of Alzheimer's disease, Vol.72(1), pp.257-269
01/01/2019
DOI: 10.3233/JAD-190176
PMID: 31561357
Abstract
Mitochondrial dysfunction is recognized as a critical component in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Deficits in oxidative capacity and, specifically, cytochrome c oxidase (CO) activity have been reported in AD brains and platelets. We previously identified a point mutation at np 9861 in AD brain mitochondrial DNA (mtDNA) that alters amino acid 219 of subunit III of CO from phenylalanine to leucine. We rapidly screened and quantitated levels of T9861C in samples using mismatched PCR-RFLP and nucleotide extension assays. Six of 40 AD brains possessed the T9861C mutation (designated AD(+)) compared to zero of 40 age-matched control brains. The 15% frequency of T9861C in AD brain is 115-fold higher than the frequency (0.13%) reported in 9,986 human mtDNA samples queried in world-wide databases. T9861C is heteroplasmic, with mutant load varying from 11% to >95%. Detected initially in parietal cortex, T9861C is not localized to that region but is also found in temporal cortex and caudate but not in hippocampus. The mutant load is unequally distributed throughout these brain regions with the highest load occurring in the parietal or temporal cortex. CO activity normalized to citrate synthase (CS) is reduced an average of 48.5% in AD(+) brains. CO/CS ratios amongst controls and the two AD populations (AD and AD+) were significantly different (p = 0.001). Post hoc differences were also significant between controls and AD(+) (p = 0.001) and controls and AD (p = 0.019). There was no significant difference between AD and AD(+) (p = 0.317).
Details
- Title: Subtitle
- The T9861C Mutation in the mtDNA-Encoded Cytochrome C Oxidase Subunit III Gene Occurs in High Frequency but with Unequal Distribution in the Alzheimer's Disease Brain
- Creators
- Frank J. Castora - Eastern Virginia Medical SchoolBarbara L. Conyers - Eastern Virginia Medical SchoolBlake S. Gershon - Eastern Virginia Medical SchoolKimberly A. Kerns - Eastern Virginia Medical SchoolRobert Campbell - Eastern Virginia Medical SchoolFatma Simsek-Duran - Eastern Virginia Medical School
- Resource Type
- Journal article
- Publication Details
- Journal of Alzheimer's disease, Vol.72(1), pp.257-269
- Publisher
- Ios Press
- DOI
- 10.3233/JAD-190176
- PMID
- 31561357
- ISSN
- 1387-2877
- eISSN
- 1875-8908
- Number of pages
- 13
- Grant note
- Commonwealth Health Research Board Virginia Center of Aging Alzheimer's and Related Diseases Research Award Foundation
- Language
- English
- Date published
- 01/01/2019
- Academic Unit
- Psychiatry
- Record Identifier
- 9984296259302771
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