DNA Repair in Huntington's Disease and Spinocerebellar Ataxias: Somatic Instability and Alternative Hypotheses.
Huntington’s disease
N6-furfuryladenine
disease modifiers
genome wide analysis studies
somatic expansion
Journal
Journal of Huntington's disease
ISSN: 1879-6400
Titre abrégé: J Huntingtons Dis
Pays: Netherlands
ID NLM: 101589965
Informations de publication
Date de publication:
2021
2021
Historique:
entrez:
13
2
2021
pubmed:
14
2
2021
medline:
17
11
2021
Statut:
ppublish
Résumé
The use of genome wide association studies (GWAS) in Huntington's disease (HD) research, driven by unbiased human data analysis, has transformed the focus of new targets that could affect age at onset. While there is a significant depth of information on DNA damage repair, with many drugs and drug targets, most of this development has taken place in the context of cancer therapy. DNA damage repair in neurons does not rely on DNA replication correction mechanisms. However, there is a strong connection between DNA repair and neuronal metabolism, mediated by nucleotide salvaging and the poly ADP-ribose (PAR) response, and this connection has been implicated in other age-onset neurodegenerative diseases. Validation of leads including the mismatch repair protein MSH3, and interstrand cross-link repair protein FAN1, suggest the mechanism is driven by somatic CAG instability, which is supported by the protective effect of CAA substitutions in the CAG tract. We currently do not understand: how somatic instability is triggered; the state of DNA damage within expanding alleles in the brain; whether this damage induces mismatch repair and interstrand cross-link pathways; whether instability mediates toxicity, and how this relates to human ageing. We discuss DNA damage pathways uncovered by HD GWAS, known roles of other polyglutamine disease proteins in DNA damage repair, and a panel of hypotheses for pathogenic mechanisms.
Identifiants
pubmed: 33579859
pii: JHD200414
doi: 10.3233/JHD-200414
pmc: PMC7990435
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
165-173Subventions
Organisme : CIHR
Pays : Canada
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