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

Lulu Jiang, Weiwei Lin, Cheng Zhang, Peter E.A. Ash, Mamta Verma, Julian Kwan, Emily van Vliet, Zhuo Yang, Anna Lourdes Cruz, Samantha Boudeau, Brandon F. Maziuk, Shuwen Lei, Jaehyup Song, Victor E. Alvarez, Stacy Hovde, Jose F. Abisambra, Min Hao Kuo, Nicholas Kanaan, Melissa E. Murray, John F. CraryJian Zhao, Ji Xin Cheng, Leonard Petrucelli, Hu Li, Andrew Emili, Benjamin Wolozin

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)4209-4227.e12
JournalMolecular Cell
Issue number20
StatePublished - Oct 21 2021


  • Alzheimer's disease
  • METTL3
  • RNA methylation
  • RNA translation
  • fibrils
  • lamin
  • neurodegeneration
  • nuclear envelope
  • stress granules
  • tau oligomerization

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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