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Fig. 5 | Acta Neuropathologica Communications

Fig. 5

From: Pathological tau drives ectopic nuclear speckle scaffold protein SRRM2 accumulation in neuron cytoplasm in Alzheimer’s disease

Fig. 5

Nuclear Speckle disruption occurs as a result of pathological tau in AD. a Changes associated with aging, including decreased proteostasis, increased neuroinflammation, and metabolic challenge, contribute to the initiation of amyloid plaque deposition. Plaques have been shown to trigger a tauopathy cascade. Here we demonstrate that pathological tau deposition coincides with depletion of nuclear speckle scaffold protein SRRM2 from the nucleus. Nuclear SRRM2 function within nuclear speckles is required for appropriate mRNA processing. Inefficient mRNA processing causes neurodegeneration. b Phosphorylation of SRRM2 at pS1068 drives SRRM2 transit from the nucleus to cytoplasm and we propose that pathological tau provokes phosphorylation and mislocalization of SRRM2 through an ER stress and ERK1/2 mediated pathway which leads to neurodegeneration. c 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. We propose that the sut RNA binding protein pathway modulates tauopathy by restoring nuclear speckle function in the face of pathological tau

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