Altered tau isoform ratio caused by loss of FUS and SFPQ function leads to FTLD-like phenotypes

Fused in sarcoma (FUS) and splicing factor, prolineandglutamine-rich (SFPQ) are RNA binding proteinsthat regulate RNA metabolism. We found that alternativesplicing of the Mapt gene at exon 10, whichgenerates 4-repeat tau (4R-T) and 3-repeat tau(3R-T), is regulated by interactions between FUSand SFPQ in the nuclei of neurons. HippocampusspecificFUS- or SFPQ-knockdown mice exhibitfrontotemporal lobar degeneration (FTLD)-like behaviors,reduced adult neurogenesis, accumulationof phosphorylated tau, and hippocampal atrophywith neuronal loss through an increased 4R-T/3R-Tratio. Normalization of this increased ratio by 4R-Tspecificsilencing results in recovery of the normalphenotype. These findings suggest a biological linkamong FUS/SFPQ, tau isoform alteration, andphenotypic expression, which may function in theearly pathomechanism of FTLD