Loss of interruption in the HTT CAG repeat is associated with increased somatic expansion and loss of medium spiny neurons in HD

Abstract Synonymous loss of interruption variants in the expanded CAG repeat sequence of Huntingtin ( HTT ) accelerate the clinical onset and progression of Huntington disease (HD). Medium spiny neurons (MSNs) are gradually lost in HD and undergo selective somatic CAG expansion, but it is unclear how CAG expansion in MSNs relates to HD pathology. Here, we show that MSNs with large (111-150 CAG) and very large (>150 CAG) somatic expansions are rare in early manifest HD, but accumulate in proportion with duration of disease and inherited CAG repeat length. In patients with the deleterious CAG-CCG loss-of-interruption (CAG-CCG LOI) modifier, the proportion of MSNs with large and very large expansions is increased ∼5-fold despite reduced small somatic expansions in blood, and direct caudate MSN counts are reduced. Our findings suggest that increased somatic CAG expansion contributes to accelerated striatal MSN pathology and hastened onset of HD, but that MSNs with very large genomic CAG expansions can persist among surviving neurons of the HD brain.