Nuclear Speckle Protein SRRM2 Co-localized with Pathological Tau (pTauS396) in Neuronal and Glial Cells in...

Progressive Supranuclear Palsy (PSP) is a primary 4-repeat tauopathy characterized by progressive motor and cognitive decline. Like other tauopathies, tau misfolding and aggregation are prominent but yield PSP-specific features such as tufted astrocytes and globose neurofibrillary tangles. Emerging evidence suggests that nuclear speckle disassembly and mislocalization of RNA-binding proteins, including serine/arginine repetitive matrix protein 2 (SRRM2), may contribute to disease progression, though SRRM2's role in PSP remains unclear. To assess its association with tau pathology, we examined SRRM2 distribution in midbrain neurons, as well as in astrocytes from both cortical and midbrain regions, using post-mortem immunohistochemistry, immunofluorescence, and 3D reconstruction. In PSP midbrain, neuronal SRRM2 immunoreactivity was markedly elevated compared to controls and co-localized with pTauS396, with >80% overlap; co-localization strongly correlated with SRRM2 abundance (r = 0.9809, p = 0.0191). 3D analysis revealed heterogeneity across cases (PSP-1 to PSP-4) in aggregate morphology, SRRM2 levels, and tau associations. In tufted astrocytes, pTauS396 signals were detected in PSP-1 cortex and PSP-4 midbrain. SRRM2 was absent or faint, yet 3D imaging revealed near-complete SRRM2-pTauS396 co-localization (99% in PSP-1 cortex, 89% in PSP-4 midbrain), regardless of SRRM2 abundance. These findings highlight SRRM2 association with pTauS396 in tangle of PSP.