2026-09-14 カナダ・ブリティッシュコロンビア大学（UBC）
Huntington disease (HD) is an inherited, progressive disorder that causes involuntary movements and psychiatric problems.
＜関連情報＞
- https://news.ubc.ca/2026/09/why-some-huntington-disease-patients-decline-years-earlier/
- https://www.cell.com/neuron/fulltext/S0896-6273(26)00640-9
HTT CAGリピートの中断の喪失は、ハンチントン病における体細胞増殖および中型有棘ニューロンの喪失と関連している Loss of interruption in the HTT CAG repeat is associated with somatic expansion and loss of medium spiny neurons in Huntington’s disease
Chris Kay ∙ Jessica Levesley, ∙ Kert Mätlik ∙ … ∙ Richard L.M. Faull ∙ Nathaniel Heintz ∙ Michael R. Hayden
Neuron Published:September 14, 2026
DOI:https://doi.org/10.1016/j.neuron.2026.08.010
Highlights
- Large somatic CAG expansions accumulate in HD-affected medium spiny neurons (MSNs)
- The CAG-CCG LOI modifier increases expansion in MSNs yet decreases expansion in blood
- The CAG-CCG LOI accelerates HD MSN loss in parallel with increased somatic expansion
- Expansion-promoting repeat sequence changes can accelerate cell-type-specific pathology
Summary
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.
