Early and progressive transcriptional remodeling of retrotransposons in Huntington’s Disease Models

Retrotransposons, including autonomous Long Interspersed Nuclear Elements (LINEs) and non-coding Short Interspersed Nuclear Elements (SINEs), are integral to genomic structure and plasticity, with emerging roles in neurodegeneration. In Huntington's disease (HD), the contribution of retrotransposable elements to pathogenesis is still poorly characterized. Here, we investigated the spatiotemporal expression profiles of LINE and SINE families in two HD mouse models (R6/2 and zQ175), across pre-symptomatic, symptomatic, and embryonic stages. Using quantitative PCR, we identified distinct, region-specific alterations in LINE and SINE expression that evolve with disease progression. Notably, dysregulation emerged as early as embryonic day 18 in zQ175 mice, marked by selective downregulation of L1 5′UTR Tf and massive increase in SINE B2. Symptomatic stages revealed model- and region-dependent patterns, including upregulation of specific LINEs and SINEs in striatal and cortical tissues, alongside widespread downregulation in the hippocampus. Immunoblottings showed that ORF1p and ORF2p protein levels were reduced in striatum, cortex, and hippocampus of symptomatic HD mice, often dissociating from transcriptional changes. Our results demonstrate that retrotransposon dysregulation is an early and progressive event in HD, preceding overt neurodegeneration and reflecting regional vulnerability. These findings support the hypothesis that retrotransposable element mobilization may contribute to HD pathogenesis likely representing a novel therapeutic target.