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

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.