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

Evan Lester1, Felicia K Ooi2, Nadine Bakkar3, Jacob Ayers4, Amanda L Woerman5, Joshua Wheeler6, Robert Bowser3, George A Carlson4, Stanley B Prusiner7, Roy Parker8

  1. Department of Biochemistry, University of Colorado, Boulder, CO, USA; Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  2. Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
  3. Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ, USA.
  4. Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA; Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
  5. Department of Biology and Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, MA, USA.
  6. Department of Biochemistry, University of Colorado, Boulder, CO, USA; Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Pathology, Stanford University, Stanford, CA, USA.
  7. Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA; Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA.
  8. Department of Biochemistry, University of Colorado, Boulder, CO, USA; Howard Hughes Medical Institute, University of Colorado, Boulder, CO, USA. Electronic address: roy.parker@colorado.edu.

Abstract

Tau aggregates contribute to neurodegenerative diseases, including frontotemporal dementia and Alzheimer's disease (AD). Although RNA promotes tau aggregation in vitro, whether tau aggregates in cells contain RNA is unknown. We demonstrate, in cell culture and mouse brains, that cytosolic and nuclear tau aggregates contain RNA with enrichment for small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs). Nuclear tau aggregates colocalize with and alter the composition, dynamics, and organization of nuclear speckles, membraneless organelles involved in pre-mRNA splicing. Moreover, several nuclear speckle components, including SRRM2, mislocalize to cytosolic tau aggregates in cells, mouse brains, and brains of individuals with AD, frontotemporal dementia (FTD), and corticobasal degeneration (CBD). Consistent with these alterations, we observe that the presence of tau aggregates is sufficient to alter pre-mRNA splicing. This work identifies tau alteration of nuclear speckles as a feature of tau aggregation that may contribute to the pathology of tau aggregates.

Presented By Evan Lester | ORCID iD

Neuroscience, Biochemistry, MedicineNicholas Liao2021-05 (May)