HNRNPA2B1 Mediates the Association of Oligomeric Tau with N 6-Methyladenosine and Neurodegeneration

We combine optogenetics with proteomics for time-resolved identification of tau oligomer (oTau) protein interactomes. Optically induced tau oligomerization is elicits a translational stress response exhibiting increased cytoplasmic localization of N6-methyladenosine (m6A) modified transcripts that partially co-localize with oTau, stress granules composed of HNRNPA2B1 and TIA1 but not G3BP1. Appearance of the cytoplasmic m6A complex occurs with a concomitant reduction in protein synthesis. Persistent tau oligomerization elicits neurodegeneration. We show that cytoplasmic translocation of m6A labeled transcripts is a prominent neuropathological feature of tauopathy in P301S tau mice and Alzheimer’s disease brain. Characterization of the oTau proteome identifies the RNA binding protein, HNRNPA2B1 as a principle target of oTau. Knockdown of HNRNPA2B1 abrogates the association of oTau with m6A-labeled transcripts, preventing the oTau-induced reduction in protein synthesis and reducing neurodegeneration. These results suggest that oTau elicits stress and toxicity through binding to HNRNPA2B1, which functions as a reader of m6A-labeled transcripts.