Extensive transcriptomic changes in cellular and animal models of Huntington's disease depending on the length of CAG repeats in the exon 1 of the HTT gene.

Abstract

Although Huntington's disease - a severe, inherited, neurodegenerative disorder - is primarily caused by a pathological variant of the HTT gene (encoding huntingtin protein) which is characterized by the extension of CAG repeats in the 1st exon exceeding 36 triplets, the biochemical mechanisms underlying the disease remain poorly understood. Mutant huntingtin forms toxic aggregates in cells; however, the clinical symptoms usually appear in adulthood. Recent reports suggested that somatic expansion of CAG repeats to more than 150 copies may be responsible for the pathogenicity and could explain the delayed onset of symptoms in this inherited disease. Nevertheless, it remains unclear why such an expansion occurs only in cells bearing HTT alleles with the original number of CAG repeats over 36. Here, we used cellular models of Huntington disease, consisting of human HEK293 cell lines with either normal (16/17) or pathogenic (41, 53, 84) numbers of CAG repeats in exon 1 of HTT, as well as the R6/1 mouse model. Using AlphaFold3, protein structures were predicted for the human huntingtin variants, revealing significant changes in pathogenic forms compared to the normal form. Transcriptomic analyses indicated that expression of a few thousand genes is significantly dysregulated in cells with increased CAG repeat numbers. Products of these genes are involved in various processes, such as apoptosis, autophagy, and DNA repair and recombination. Thus, we suggest that stress conditions, caused by dysregulation of cellular processes, might facilitate abnormal somatic expansion of CAG repeats, contrary to cells bearing normal HTT alleles.