The study identifies CELF2 as an important regulator of tau splicing and the production of 4R tau, providing new insight into molecular mechanisms that may contribute to tau-related neurodegeneration. These findings advance our understanding of how disruptions in RNA regulation may influence neurodegenerative disease.
Ishana Syed is an Integrated Biomedical Sciences PhD student in the neuroscience discipline, mentored in the lab of Lizhen Chen, PhD. Dr. Chen is the holder of the Bartell Zachry Memorial Distinguished Professorship for Research in Neurodegenerative Diseases, an Associate Professor with the Department of Cell Systems and Anatomy, and an investigator with the Sam and Ann Barshop Institute for Longevity and Aging Studies.
CELF2 promotes 4R Tau splicing via nuclear clustering and drives cognitive dysfunction in tauopathy models
Xin Li, Ishana Syed, Rashmi Adhikari, Jing Jiang, Yu Zhang, Dan Tang, Su-Hyuk Ko, Zhao Zhang, Zhijie Liu, Lizhen Chen
Nat Commun. 2026 Jul 29;17(1):9218. doi: 10.1038/s41467-026-76241-9.
Abstract
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.