Scholarlink

<p>Expansion of CAG repeats in <i>HTT</i> exon 1 is the acknowledged driver of Huntington’s disease. Alternative processing of <i>HTT</i> pre-mRNA generates the truncated <i>HTT1a</i> transcript, translated into a toxic peptide. While its dependence on CAG length is well documented, the role of adjacent sequences - particularly the Proline-Rich Domain (PRD) - remains unexplored. Using our HuntEx1-engineered mouse embryonic stem cell platform, we show that human PRD promotes HTT1a production, whereas its replacement with mouse PRD in an otherwise human exon 1 markedly reduces HTT1a levels. Mechanistically, we find that the PRD shapes mRNA structure, and motif analysis identifies Serine-Arginine Splicing Factor 7 (SRSF7) binding sites in mouse but not in human PRD. Their targeted mutation confirms SRSF7’s regulatory role in suppressing <i>HTT1a</i> production. Our findings establish the PRD as a key <i>cis</i>-regulator of HTT1a biogenesis, demonstrating that <i>HTT</i> toxicity also depends on sequence context, and highlighting splicing-based, PRD-focused therapeutic avenues.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Human-specific sequence features in HTT exon 1 promote toxic misprocessing via splicing factor SRSF7

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月31日

查看全文
  • Camilla Maffezzini,
  • Raffaele Iennaco,
  • Andrea Scolz,
  • Simone Maestri,
  • Christian Landles,
  • Georgina F. Osborne,
  • Marta M. Bronzini,
  • Camilla Trovesi,
  • Thomas Carzaniga,
  • Luca Casiraghi,
  • Jimena Quiros Ramirez,
  • Thomas F. Vogt,
  • Dan P. Felsenfeld,
  • Tommaso Bellini,
  • Chiara Zuccato,
  • Gillian P. Bates,
  • Elena Cattaneo

摘要

Expansion of CAG repeats in HTT exon 1 is the acknowledged driver of Huntington’s disease. Alternative processing of HTT pre-mRNA generates the truncated HTT1a transcript, translated into a toxic peptide. While its dependence on CAG length is well documented, the role of adjacent sequences - particularly the Proline-Rich Domain (PRD) - remains unexplored. Using our HuntEx1-engineered mouse embryonic stem cell platform, we show that human PRD promotes HTT1a production, whereas its replacement with mouse PRD in an otherwise human exon 1 markedly reduces HTT1a levels. Mechanistically, we find that the PRD shapes mRNA structure, and motif analysis identifies Serine-Arginine Splicing Factor 7 (SRSF7) binding sites in mouse but not in human PRD. Their targeted mutation confirms SRSF7’s regulatory role in suppressing HTT1a production. Our findings establish the PRD as a key cis-regulator of HTT1a biogenesis, demonstrating that HTT toxicity also depends on sequence context, and highlighting splicing-based, PRD-focused therapeutic avenues.