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

Evan Lester; Felicia K Ooi; Nadine Bakkar; Jacob Ayers; Amanda L Woerman; Joshua Wheeler; Robert Bowser; George A Carlson; Stanley B Prusiner; Roy Parker

doi:10.1016/j.neuron.2021.03.026

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

Neuron. 2021 May 19;109(10):1675-1691.e9. doi: 10.1016/j.neuron.2021.03.026. Epub 2021 Apr 12.

Authors

Affiliations

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.

Keywords: Alzheimer's Disease; Frontemporal Dementia; MAPT; Nuclear Speckles; RNA; RNA binding proteins; SRRM2; Splicing; Tau; snRNA.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alzheimer Disease / metabolism*
Alzheimer Disease / pathology
Animals
Cell Nucleus / metabolism*
Cell Nucleus / ultrastructure
Cytosol / metabolism
Female
HEK293 Cells
Humans
Male
Mice
Mice, Inbred C57BL
Protein Binding
Protein Transport
RNA Splicing
RNA, Small Nucleolar / metabolism*
RNA-Binding Proteins / metabolism
tau Proteins / metabolism*

Substances

RNA, Small Nucleolar
RNA-Binding Proteins
SRRM2 protein, human
tau Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding