Tau aggregates are RNA-protein assemblies that mislocalize multiple nuclear speckle components

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

“…Several studies have shown that tau immunopurifies with several RNA-binding proteins [ 41 , 42 ], and recent work has nominated nuclear speckles as a participant in tauopathies through the scaffold protein SRRM2. Lester and colleagues showed that tau deposits purified from model systems, including mice and human cells, contain many RNAs and are highly enriched for small nuclear and small nucleolar RNAs (snRNAs and snoRNAs) [ 7 ]. These findings are consistent with previous work showing that tau aggregates in brain are typically RNA-positive [ 43 ], and suggest pathological properties for nuclear tau [ 42 , 44 – 46 ], as Lester and colleagues speculate pathological tau may be seeded by RNA into nuclear aggregates in human tauopathy disorders.…”

“…RNA acts as a potent initiator of tau aggregation in vitro and can decorate fibrillar tau after aggregation [ 9 – 11 ]. Most recently, tau has been shown to form aggregates with an RNA protein assembly in some cellular contexts [ 7 ]. The recruitment of RNA to tau aggregates may drive splicing defects or disrupt other nuclear functions related to RNA [ 5 – 7 , 12 ].…”

“…Most recently, tau has been shown to form aggregates with an RNA protein assembly in some cellular contexts [ 7 ]. The recruitment of RNA to tau aggregates may drive splicing defects or disrupt other nuclear functions related to RNA [ 5 – 7 , 12 ]. These observations suggest the possibility of tauopathy-driven RNA-mediated cellular dysfunction, but these phenomena have not been investigated in the context of AD pathology.…”

“…In this study, we investigated another nuclear speckle protein, SRRM2, which is a core nuclear speckle scaffold protein required for the formation of nuclear speckles. Recent studies indicate SRRM2 abnormality in AD cellular and animal models [ 7 , 22 ]. Guided by findings from molecular genetic investigations in model systems, the current study examines the impact of pathological tau on SRRM2 protein in the brains of AD patients and mouse models of tauopathy.…”

Protein Aggregation Landscape in Neurodegenerative Diseases: Clinical Relevance and Future Applications

“…Heterotypic interactions with polyanionic compounds such as nucleic acids were also reported as a way to induce tau LLPS. Indeed, a recent work demonstrated the presence of tau in nuclear speckles in association with RNA [174]. Within droplets, double electron-electron resonance spectroscopy experiments revealed that tau assumes a more extended structure, similar to that observed in anisosomes formed by TDP-43 [175].…”