Tanaka and colleagues demonstrated that abnormally localized SRRM2 occurs in both AD and animal models of Aβ deposition, driving aberrant splicing [22]. They further reported that phosphorylation of SRRM2 at pS1068 stimulates SRRM2 transit from the nucleus to cytoplasm, and hypothesized that ER stress activation of ERK1/2 drives pSRRM2 phosphorylation [22]. Here, we show that pathological tau, in the absence of Aβ, can provoke pSRRM2 accumulation in the cytoplasm in mouse models, consistent with our observation that abnormal pSRRM2 deposition coincides with severity of AD tau pathology. Recent work has also demonstrated that pathological tau drives ER stress in both animal models [34–36] and in AD [37–40]. We hypothesize a cascade where pathological tau provokes pSRRM2 mislocalization through an ER stress and ERK1/2 mediated pathway resulting in aberrant splicing and ultimately neurodegeneration (Fig. 5b).
