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<p>Alternative splicing is a fundamental mechanism underlying protein diversity. The microtubule-associated protein tau (MAPT) undergoes age-associated alternative splicing of exon 10 to generate 3 R and 4 R isoforms, and disruption of the 4 R:3 R ratio is a central feature of tauopathies. However, the molecular mechanisms regulating tau exon 10 splicing remain incompletely understood. Here we identify a clustering-based mechanism underlying tau splicing regulation by the RNA-binding protein CELF2. An intrinsically disordered region (IDR) within the CELF2 hinge domain mediates multivalent assembly and is required for splicing activity. NOVA2 and SFPQ co-cluster with CELF2 and cooperatively regulate tau exon 10 splicing. A conserved negatively charged residue, D388, is essential for CELF2 assembly, protein interactions, and splicing function. In vivo, the assembly capacity of CELF2 correlates with 4 R tau expression and influences locomotor and cognitive performance. Together, these findings support that IDR-mediated higher-order assembly of CELF2 coordinates tau splicing regulation and impacts tau-related neurodegeneration.</p>

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CELF2 promotes 4R Tau splicing via nuclear clustering and drives cognitive dysfunction in tauopathy models

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Xin Li,
  • Ishana Syed,
  • Rashmi Adhikari,
  • Jing Jiang,
  • Yu Zhang,
  • Dan Tang,
  • Su-Hyuk Ko,
  • Zhao Zhang,
  • Zhijie Liu,
  • Lizhen Chen

摘要

Alternative splicing is a fundamental mechanism underlying protein diversity. The microtubule-associated protein tau (MAPT) undergoes age-associated alternative splicing of exon 10 to generate 3 R and 4 R isoforms, and disruption of the 4 R:3 R ratio is a central feature of tauopathies. However, the molecular mechanisms regulating tau exon 10 splicing remain incompletely understood. Here we identify a clustering-based mechanism underlying tau splicing regulation by the RNA-binding protein CELF2. An intrinsically disordered region (IDR) within the CELF2 hinge domain mediates multivalent assembly and is required for splicing activity. NOVA2 and SFPQ co-cluster with CELF2 and cooperatively regulate tau exon 10 splicing. A conserved negatively charged residue, D388, is essential for CELF2 assembly, protein interactions, and splicing function. In vivo, the assembly capacity of CELF2 correlates with 4 R tau expression and influences locomotor and cognitive performance. Together, these findings support that IDR-mediated higher-order assembly of CELF2 coordinates tau splicing regulation and impacts tau-related neurodegeneration.