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

Abstract

Several conserved nuclear RNA binding proteins (sut-1, sut-2, and parn-2) control tau aggregation and toxicity in C. elegans, mice, and human cells. MSUT2 protein normally resides in nuclear speckles, membraneless organelles composed of phase-separated RNAs and RNA-binding proteins that mediate critical steps in mRNA processing including mRNA splicing. We used human pathological tissue and transgenic mice to identify Alzheimer’s disease-specific cellular changes related to nuclear speckles. We observed that nuclear speckle constituent scaffold protein SRRM2 is mislocalized and accumulates in cytoplasmic lesions in AD brain tissue. Furthermore, progression of tauopathy in transgenic mice is accompanied by increasing mislocalization of SRRM2 from the neuronal nucleus to the soma. In AD brain tissue, SRRM2 mislocalization associates with increased severity of pathological tau deposition. These findings suggest potential mechanisms by which pathological tau impacts nuclear speckle function in diverse organisms ranging from C. elegans to mice to humans. Future translational studies aimed at restoring nuclear speckle homeostasis may provide novel candidate therapeutic targets for pharmacological intervention.

Cytosolic condensates enriched in polyserine repeats are preferred sites of tau fiber propagation

“…Thus, polyserine alone is sufficient to mediate associations with tau aggregate in a length dependent manner. This provides a molecular explanation for the recruitment of the polyserine containing SRRM2 protein to tau aggregates in cell line and mouse models, as well as in patient samples (Lester et al, 2021;McMillan et al, 2021). Interestingly we also observed that 42, 20, 10, and 5-serine-Halo produced cytoplasmic foci that were not present in Halo alone (Figure 3A), suggesting polyserine has self-assembly properties (see below).…”

“…Thus, polyserine alone is sufficient to mediate associations with tau aggregate in a length dependent manner. This provides a molecular explanation for the recruitment of the polyserine containing SRRM2 protein to tau aggregates in cell line and mouse models, as well as in patient samples (Lester et al, 2021; McMillan et al, 2021).…”

“…Further, polyserine repeats alone are sufficient for targeting to tau aggregates in a length dependent manner (Figure 3). The association of polyserine with tau aggregates provides a molecular explanation for the mislocalization of SRRM2 to pathogenic tau inclusions in post-mortem samples from AD, CBD, and FTLD patients (Lester et al, 2021; McMillan et al, 2021).…”

“…Two of the most prominently mislocalized proteins are pinin (PNN) and serine/arginine repetitive matrix protein 2 (SRRM2). The mislocalization of SRRM2 to cytoplasmic tau aggregates is relevant to disease since this occurs in tau mouse models of disease and tauopathy patient brains (Lester et al, 2021; McMillan et al, 2021). Congruent with these findings, SRRM2 is an RNA binding protein involved in RNA splicing and RNA sequencing shows tau aggregation induces RNA splicing changes in several model systems (Apicco et al, 2019; Lester et al, 2021), as well as in patients with AD (Hsieh et al, 2019; Raj et al, 2018).…”

Disruption of nuclear envelope integrity as a possible initiating event in tauopathies

“…We found that reducing the expression of BANF1 or ANKLE2 caused mislocalization of nuclear speckle component SRRM2 even without tau aggregation. Thus, the loss of nuclear envelope components alone initiated an event associated with tau pathogenesis in Alzheimer's disease (McMillan et al, 2021). Similarly, the disruption of Banf1, Ankle2, or Ppp2ca in mouse cortical neurons increased P-tau-Ser356 in the perinuclear and nuclear domains.…”