Cell-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…

• UD
  U.S. Department of Veterans Affairs
• HD
  Hereditary Disease Foundation
• CF
  CHDI Foundation
• CH
  Cure Huntington's Disease Initiative
• UO
  University of Michigan

  Award: P30AG072931
• UO
  University of Washington
• SJ
  Sigrid Juséliuksen Säätiö
• NI
  National Institutes of Health

  Awards: P30AG066462, P30AG072931, P30AG053760, AG066509
• CI
  Canadian Institutes of Health Research

  Awards: FRN-173282, FRN-148910, FRN-388879
• NS
  Natural Sciences and Engineering Research Council of Canada

  Awards: RGPIN-2016-06355/498835, RGPIN-2016-08355