We previously identified RNA binding proteins that reside in nuclear speckles, including sut-1, sut-2/MSUT2, and parn-2/TOE1. Examination of genes required for tau pathology-driven neurodegeneration in C. elegans uncovered suppressor of tauopathy 1 (sut-1), a nuclear speckle resident protein whose loss of function prevents tau-mediated neurodegeneration; sut-1 functions in speckles and plays a role in C. elegans trans-splicing [14]. The same genetic approach uncovered sut-2 as a genetic suppressor of tauopathy [16], and subsequent translational studies revealed that the mammalian homolog of sut-2 (MSUT2) also resides in nuclear speckles and plays a critical role in tau aggregation and neurodegeneration in mice, human cells, and AD brain tissue [19, 25]. Recent studies of other nuclear speckle resident proteins revealed that the nuclear speckle resident RNA nucleases parn-1/PARN and parn-2/TOE1 play distinct roles in tau toxicity [15]. Contemporaneous work from other laboratories has also implicated RNA-binding proteins in tauopathy, including Musashi (MSI) and T-cell intracellular antigen 1 (TIA1); while they have divergent RNA-binding functions, both TIA1 and MSI co-localize with tau-containing cytoplasmic lesions and modulate tau aggregation and concomitant tauopathy phenotypes in model systems [30–33].
