Tissue-specific somatic expansion of the mutant Huntingtin (mHTT) CAG tract and regional degeneration of the brain are key features of Huntington's disease (HD). However, the relationships between somatic CAG expansion, death of specific cell types, and molecular events associated with these processes have not been established. Here we employed 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. Expansion of the mHTT CAG tract occurs in striatal MSNs and cholinergic interneurons, in cerebellar Purkinje cells, and at the mutant ATXN3 locus in MSN nuclei from SCA3 donors. Somatic CAG tract instability in MSNs is associated with higher levels of MSH2 and MSH3. Our data indicate that somatic CAG tract expansion is not sufficient for cell death, and identify transcriptional changes associated with somatic CAG expansion and toxicity in the human striatum.
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