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Updated: Oct 31, 2025
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Pathological tau drives ectopic nuclear speckle scaffold protein SRRM2 accumulation in neuron cytoplasm in
Pamela J McMillan1,2, Timothy J Strovas1, Misa Baum1
1Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, S182, 1660 South Columbian Way, Seattle, WA, 98108, USA.
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.
Insights
Nuclear RNA binding proteins influence tau aggregation. In Alzheimer's disease, SRRM2 protein mislocalizes from nuclear speckles to the cytoplasm, correlating with tau pathology severity.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Conserved nuclear RNA binding proteins (sut-1, sut-2, parn-2) regulate tau aggregation and toxicity across species.
- Nuclear speckles, sites of mRNA processing, contain RNA-binding proteins like MSUT2.
- Alzheimer's disease (AD) involves tau pathology and potential disruptions in nuclear function.
Purpose of the Study:
- To investigate Alzheimer's disease-specific changes in nuclear speckles.
- To identify the role of SRRM2, a nuclear speckle scaffold protein, in AD pathogenesis.
- To explore the link between pathological tau and nuclear speckle integrity.
Main Methods:
- Analysis of human pathological brain tissue from AD patients.
- Utilizing transgenic mouse models of tauopathy.
- Immunohistochemical and cellular localization studies of SRRM2 and tau.
Main Results:
- SRRM2, a nuclear speckle protein, was found mislocalized and accumulated in cytoplasmic lesions in AD brain tissue.
- In transgenic mice, SRRM2 mislocalization from the nucleus to the soma increased with tauopathy progression.
- SRRM2 mislocalization in AD brain correlated with increased severity of pathological tau deposition.
Conclusions:
- Pathological tau in Alzheimer's disease disrupts nuclear speckle function, evidenced by SRRM2 mislocalization.
- This disruption occurs across diverse organisms, suggesting conserved mechanisms.
- Restoring nuclear speckle homeostasis presents a potential therapeutic strategy for AD.
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