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.


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*


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