Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy

Mol Cell. 2021 Oct 21;81(20):4209-4227.e12. doi: 10.1016/j.molcel.2021.07.038. Epub 2021 Aug 27.

Abstract

The microtubule-associated protein tau oligomerizes, but the actions of oligomeric tau (oTau) are unknown. We have used Cry2-based optogenetics to induce tau oligomers (oTau-c). Optical induction of oTau-c elicits tau phosphorylation, aggregation, and a translational stress response that includes stress granules and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau-c. The association of HNRNPA2B1 with endogenous oTau was verified in neurons, animal models, and human Alzheimer brain tissues. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N6-methyladenosine (m6A) modified RNA transcripts. Knockdown of HNRNPA2B1 prevents oTau or oTau-c from associating with m6A or from reducing protein synthesis and reduces oTau-induced neurodegeneration. Levels of m6A and the m6A-oTau-HNRNPA2B1 complex are increased up to 5-fold in the brains of Alzheimer subjects and P301S tau mice. These results reveal a complex containing oTau, HNRNPA2B1, and m6A that contributes to the integrated stress response of oTau.

Keywords: Alzheimer's disease; METTL3; RNA methylation; RNA translation; fibrils; lamin; neurodegeneration; nuclear envelope; stress granules; tau oligomerization.

Publication types

  • Research Support, N.I.H., Extramural
  • Video-Audio Media

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Animals
  • Case-Control Studies
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / pathology*
  • Disease Models, Animal
  • Disease Progression
  • Female
  • HEK293 Cells
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism*
  • Humans
  • Male
  • Methylation
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • Protein Aggregates
  • Protein Aggregation, Pathological
  • RNA / genetics
  • RNA / metabolism*
  • RNA Processing, Post-Transcriptional*
  • Severity of Illness Index
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • MAPT protein, human
  • Protein Aggregates
  • hnRNP A2
  • tau Proteins
  • RNA
  • N-methyladenosine
  • Adenosine