Multiple studies have demonstrated that tau neuropathology drives neurodegeneration by causing dysfunction of nuclear RNA processing events (reviewed in [48]). Recently, tau aggregates have been shown to disrupt the nuclear pore complex, blocking export of mRNAs via nuclear depletion and co-aggregation of tau with the disordered region of Nup98 [49]. This molecular phenotype is reminiscent of the findings reported here for pSRRM2, which is co-deposited with pathological tau. Subsequent related work in model systems has shown clear evidence for mRNA accumulation within nuclear invaginations caused by pathological tau, further supporting disruption of RNA trafficking as a critical pathological consequence of tau aggregation [6]. Other studies have implicated defects in mRNA splicing as a critical nuclear process disrupted in AD specifically nominating disruption of U1 snRNP via mislocalization of the RNA binding protein U1-70 K [42, 50, 51]. Further, tau mediated spliceosome dysfunction has been hypothesized as a trigger of cryptic RNA splicing and consequent neurodegeneration in AD [12].
