HuR modulates disease-relevant alternative splicing of MAPT and other Alzheimer's disease-related genes

Alternative splicing of MAPT exon 10 generates 4R- and 3R-Tau isoforms, and its dysregulation is associated with tauopathies including Alzheimer's disease (AD), for which effective treatments remain lacking. Here, we identify HuR as a novel repressor of MAPT exon 10 alternative splicing. Mechanistically, the RRM1 domain of HuR is critical for mediating its splicing inhibitory effect. HuR binds to the U-rich region downstream of intron 9 in MAPT together with FUBP1, KHSRP, hnRNPD, hnRNPAB, hnRNPDL, and TIAL1. The expression of HuR shows a negative association with that of FUBP1, KHSRP, hnRNPD, and TIAL1. Finally, we demonstrate that HuR regulates the expression and alternative splicing of genes involved in autophagy and apoptosis, pathways dysregulated in AD. Collectively, these findings establish HuR as a regulator of AD-relevant transcriptomic networks and provide a mechanistic basis for exploring HuR-targeted strategies in AD.