A recurring theme in tau mediated neurodegeneration is the depletion of an essential RNA-binding protein from the nucleus as a result of co-aggregation with cytoplasmic pathological tau. We reiterate this has been shown to occur for pSRRM2 (this study & [7]), Nup98 [49], and U1-70 k [42, 50, 51]; the loss of function for any one of these three critical proteins likely dooms a neuron to degeneration. However, previous genetic studies have demonstrated rescue of tauopathy phenotypes by loss of function mutations in RNA-binding proteins. Modulation of nuclear speckle content via loss of regulatory RNA-binding proteins resident in nuclear speckles, such as SUT-1 or SUT-2/MSUT2, can fully rescue tauopathy phenotypes in model systems including tau transgenic C. elegans, human cells and mouse brains [16, 19, 25]. We hypothesize that the sut RNA-binding protein pathway modulates tauopathy by restoring nuclear speckle function in the face of pathological tau (Fig. 5c).
