Chris Kay, Jessica Levesley, Kert Mätlik, Hailey Findlay Black, Emily Harvey, Stephanie Bortnick, Kyla Javier, Christina Buchanan, Tanushri Soomarooah, Inês Caldeira Brás, Glen Sequiera, Mahmoud Pouladi, Larissa Arning, Hoa H P Nguyen, Richard Roxburgh, Maurice Curtis, Richard L M Faull, Nathaniel Heintz, Michael R Hayden
Synonymous loss-of-interruption variants in the expanded CAG repeat sequence of Huntingtin (HTT) accelerate the clinical onset and progression of Huntington's disease (HD). Medium spiny neurons (MSNs) are gradually lost in HD and undergo selective somatic CAG expansion, but it is unclear how somatic expansion relates to MSN 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. 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 caudate MSN counts are reduced. Our findings suggest that increased somatic CAG expansion contributes to accelerated striatal MSN pathology and onset of HD but that MSNs with very large genomic CAG expansions can persist among surviving neurons of the HD brain.