Pathological tau drives ectopic nuclear speckle scaffold protein SRRM2 accumulation in neuron cytoplasm in Alzheimer’s disease
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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.
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In vitro studies using soluble phospho-tau oligomers find substantial alterations in nuclear-cytoplasmic transport.
“Not only is there clear morphological evidence of nuclear alterations in AD, but also, in vitro studies using soluble phospho-tau oligomers as a perturbant find substantial alterations in nuclear–cytoplasmic transport (e.g., 31, 33, 37, 54).”
From All the Tau We Cannot See (2023) · cites this paper as [37]
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The Nuclear Speckles Protein SRRM2 Is Exposed on the Surface of Cancer Cells
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- Authors
- McMillan, P. J., Strovas, T. J., Baum, M., Mitchell, B. K., Eck, R. J., Hendricks, N., Wheeler, J. M., Latimer, C. S., Keene, C. D., & Kraemer, B. C.
- Affiliations
- University of Washington (US)
- VA Puget Sound Health Care System (US)
- Corresponding author
- Kraemer, Brian C.
- ORCID
- Venue
- Acta Neuropathologica Communications
- Published
- 2021-06-29
- Volume
- 9
- Issue
- 1
- Pages
- 117-117
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC8243890
- OpenAlex
- W3173689544
- Cited by
- 64
- References
- 53
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 14 · 2023: 14 · 2022: 14 · 2021: 1
- FWCI
- 7.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Veterans Affairs
- National Institute on Aging (RF1 AG055474, K08 AG065426, P30 AG0066509)
- National Institute of Neurological Disorders and Stroke (R01NS064131)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- SRRM2, nuclear speckles, tau pathology, Alzheimer's disease, tauopathy, nuclear RNA-binding proteins, protein mislocalization, cytoplasmic accumulation, biomolecular condensates, mRNA splicing, transgenic mouse model, therapeutic target
- MeSH terms
- Nuclear Speckles, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Cytoplasm, Female, Humans, Male, Mice, Transgenic, Middle Aged, Neurons, RNA-Binding Proteins, tau Proteins, Mice
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