We observed ectopic accumulation of the nuclear speckle scaffold protein SRRM2 in the cytoplasm in AD, and pSRRM2 + deposits overlap with the neurofibrillary tangle pathology in AD. To investigate the relationship between pathological tau and ectopic SRRM2, we employed robust animal models of pathological tau deposition and found that pSRRM2 became progressively recruited to the cytoplasm as pathological tau deposition increased. In addition, pathological tau and pSRRM2 + deposits co-localize within the neuronal soma and remain in close proximity within tangle bearing neurons. Taken together, these findings support a tauopathy cascade model whereby Aβ, aging, or some other stimulus triggers pathological tau deposition in the cytoplasm, which recruits pSRRM2 to the fibrillar tau deposits leading to dysfunction of nuclear speckles (Fig. 5a).
