Selective striatal pathological changes in a novel human HTT exon 1 knock-in mouse model of Huntington's disease

Abstract

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by progressive motor deficits, cognitive decline, and psychiatric disturbances caused by expanded CAG repeats in the huntingtin gene (HTT). Despite the development of various animal models, achieving a comprehensive model that closely replicates the biological mechanisms in order to test therapeutic modalities remains a challenge. Here, we describe a novel human HTT exon 1 knock-in (HEKI-150Q) mouse model that incorporates a 3.465-kb human HTT sequence with 150 polyglutamine and successfully mimics key aspects of HD. Behavioral analysis revealed motor dysfunction, hyperactivity, and cognitive deficits similar to those observed in a human HD clinical manifestation. HEKI-150Q mice exhibited age-dependent motor impairment progression with significant phenotypic changes observed starting at six months of age. Histopathological analysis demonstrated the accumulation of mutant huntingtin aggregates, selective striatal neuronal dysfunction, and increased gliosis, further confirming the model's validity for HD research. HEKI-150Q mice thus provide a valuable tool for studying the pathogenic mechanisms of HD and testing potential therapeutic strategies, particularly those targeting human HTT exon 1.

Keywords: CRISPR-Cas9; Huntington's disease; Knock-in; Mouse model.