Distinct mismatch-repair complex genes set neuronal CAG-repeat expansion rate to drive selective pathogenesis in HD mice
University of California, Los Angeles · Neurobehavioral Systems · +1 more institution
Abstract
Huntington's disease (HD) modifiers include mismatch-repair (MMR) genes, but their connections to neuronal pathogenesis remain unclear. Here, we genetically tested 9 HD genome-wide association study (GWAS)/MMR genes in mutant Huntingtin (mHtt) mice with 140 inherited CAG repeats (Q140). Knockout (KO) of genes encoding a distinct MMR complex either strongly (Msh3 and Pms1) or moderately (Msh2 and Mlh1) rescues phenotypes with early onset in striatal medium-spiny neurons (MSNs) and late onset in the cortical neurons: somatic CAG-repeat expansion, transcriptionopathy, and mHtt aggregation. Msh3 deficiency ameliorates open-chromatin dysregulation in Q140 neurons. Mechanistically, the fast linear rate of mHtt…
Citation impact
- FWCI
- 28.35
- Percentile
- 100%
- References
- 101
Authors
19- NWNan WangCorresponding
University of California, Los Angeles, Neurobehavioral Systems
- SZShasha Zhang
University of California, Los Angeles, Neurobehavioral Systems
- PLPeter Langfelder
University of California, Los Angeles, Neurobehavioral Systems
- LRLalini Ramanathan
University of California, Los Angeles, Neurobehavioral Systems
- FGFuying Gao
University of California, Los Angeles, Neurobehavioral Systems
Topics & keywords
- Biology
- Pathogenesis
- Gene
- Genetics
- Set (abstract data type)
- Cell biology
- Immunology