Accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in Huntington's disease.
Huntington’s disease
mitochondrial DNA
sequencing
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
27 07 2021
27 07 2021
Historique:
entrez:
24
7
2021
pubmed:
25
7
2021
medline:
15
12
2021
Statut:
ppublish
Résumé
Mitochondrial dysfunction is found in the brain and peripheral tissues of patients diagnosed with Huntington's disease (HD), an irreversible neurodegenerative disease of which aging is a major risk factor. Mitochondrial function is encoded by not only nuclear DNA but also DNA within mitochondria (mtDNA). Expansion of mtDNA heteroplasmies (coexistence of mutated and wild-type mtDNA) can contribute to age-related decline of mitochondrial function but has not been systematically investigated in HD. Here, by using a sensitive mtDNA-targeted sequencing method, we studied mtDNA heteroplasmies in lymphoblasts and longitudinal blood samples of HD patients. We found a significant increase in the fraction of mtDNA heteroplasmies with predicted pathogenicity in lymphoblasts from 1,549 HD patients relative to lymphoblasts from 182 healthy individuals. The increased fraction of pathogenic mtDNA heteroplasmies in HD lymphoblasts also correlated with advancing HD stages and worsened disease severity measured by HD motor function, cognitive function, and functional capacity. Of note, elongated CAG repeats in
Identifiants
pubmed: 34301881
pii: 2014610118
doi: 10.1073/pnas.2014610118
pmc: PMC8325154
pii:
doi:
Substances chimiques
DNA, Mitochondrial
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2021 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
Competing interest statement: P.J.S., Y.W., X.G., K.Y., and Z.G. are affiliated with Cornell University.
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