biostudies-literatureMatlik KCure Huntington’s Disease InitiativeGouvernement du Canada | Natural Sciences and Engineering Research Council of CanadaNIA NIH HHSSigrid Juséliuksen SäätiöHereditary Disease FoundationGouvernement du Canada | Canadian Institutes of Health Research383-394https://www.ebi.ac.uk/biostudies/studies/S-EPMC10937393biostudies-literatureUnknown56(3)Brain region-specific degeneration and somatic expansions of the mutant Huntingtin (mHTT) CAG tract are key features of Huntington's disease (HD). However, the relationships among CAG expansions, death of specific cell types and molecular events associated with these processes are not established. Here, we used fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of cell types of the human striatum and cerebellum in HD and control donors. CAG expansions arise at mHTT in striatal medium spiny neurons (MSNs), cholinergic interneurons and cerebellar Purkinje neurons, and at mutant ATXN3 in MSNs from SCA3 donors. CAG expansions in MSNs are associated with higher levels of MSH2 and MSH3 (forming MutSβ), which can inhibit nucleolytic exciNature geneticsCell-type-specific CAG repeat expansions and toxicity of mutant Huntingtin in human striatum and cerebellum.PMC10937393P30 AG072931P30 AG066462U19 AG066567P30 AG053760FRN-388879RGPIN-2016-06355/498835P30 AG066509Caron MCPearson CEKus LDeshmukh ALMatlik KPaul MRBaffuto MMasson JYHeintz NDavis DACarroll TSfalseCell-type-specific CAG repeat expansions and toxicity of mutant Huntingtin in human striatum and cerebellum.Brain region-specific degeneration and somatic expansions of the mutant Huntingtin (mHTT) CAG tract are key features of Huntington's disease (HD). However, the relationships among CAG expansions, death of specific cell types and molecular events associated with these processes are not established. Here, we used fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of cell types of the human striatum and cerebellum in HD and control donors. CAG expansions arise at mHTT in striatal medium spiny neurons (MSNs), cholinergic interneurons and cerebellar Purkinje neurons, and at mutant ATXN3 in MSNs from SCA3 donors. CAG expansions in MSNs are associated with higher levels of MSH2 and MSH3 (forming MutSβ), which can inhibit nucleolytic exci2024-01-01T00:00:00Z2024 Mar2026-07-15T13:51:33.414Z2026-07-05T03:11:27.634ZS-EPMC109373933829133410.1038/s41588-024-01653-6