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McMillan PJ, Strovas TJ, Baum M, et al. Pathological tau drives ectopic nuclear speckle scaffold protein SRRM2 accumulation in neuron cytoplasm in Alzheimer's disease. Acta Neuropathol Commun. 2021;9(1):117doi: 10.1186/s40478-021-01219-1.
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. (2021). Pathological tau drives ectopic nuclear speckle scaffold protein SRRM2 accumulation in neuron cytoplasm in Alzheimer's disease. Acta neuropathologica communications, 9(1), 117. https://doi.org/10.1186/s40478-021-01219-1
McMillan, Pamela J, et al. "Pathological tau drives ectopic nuclear speckle scaffold protein SRRM2 accumulation in neuron cytoplasm in Alzheimer's disease." Acta neuropathologica communications vol. 9,1 (2021): 117. doi: https://doi.org/10.1186/s40478-021-01219-1
McMillan PJ, Strovas TJ, Baum M, Mitchell BK, Eck RJ, Hendricks N, Wheeler JM, Latimer CS, Keene CD, Kraemer BC. Pathological tau drives ectopic nuclear speckle scaffold protein SRRM2 accumulation in neuron cytoplasm in Alzheimer's disease. Acta Neuropathol Commun. 2021 Jun 29;9(1):117. doi: 10.1186/s40478-021-01219-1. PMID: 34187600; PMCID: PMC8243890.
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Acta Neuropathol Commun. 2021 Jun 29;9(1):117. doi: 10.1186/s40478-021-01219-1.

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

Acta neuropathologica communications

Pamela J McMillan, Timothy J Strovas, Misa Baum, Brooke K Mitchell, Randall J Eck, Nzinga Hendricks, Jeanna M Wheeler, Caitlin S Latimer, C Dirk Keene, Brian C Kraemer

Affiliations

  1. Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, S182, 1660 South Columbian Way, Seattle, WA, 98108, USA.
  2. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, 98195, USA.
  3. Graduate Program in Neuroscience, University of Washington, Seattle, WA, 98195, USA.
  4. Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, 98104, USA.
  5. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98195, USA.
  6. Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, S182, 1660 South Columbian Way, Seattle, WA, 98108, USA. [email protected].
  7. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, 98195, USA. [email protected].
  8. Graduate Program in Neuroscience, University of Washington, Seattle, WA, 98195, USA. [email protected].
  9. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98195, USA. [email protected].
  10. Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, 98104, USA. [email protected].

PMID: 34187600 PMCID: PMC8243890 DOI: 10.1186/s40478-021-01219-1

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.

Keywords: Alzheimer’s disease; MSUT2; MapT tauopathy PS19; Nuclear speckles; PABPN1; SC-35; SRRM2; Tau; ZC3H14

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