A Complex Containing HNRNPA2B1 and N6-methyladenosine Modified Transcripts Mediates Actions of Toxic Tau Oligomers

SummaryThe microtubule associated protein tau oligomerizes in response to stress and disease, but the function of oligomeric tau (oTau) and the ultimate mechanisms of toxicity are unknown. To gain insights, we have now used Cry2-based optogenetics to induce tau oligomers (oTau-c) in neuronal cultures. oTau-c can seed tau aggregation and biochemical fractionates in a manner similar to oTau. Optical induction of oTau elicits a translational stress response that includes cytoplasmic translocation of the TIA1, abundant stress granules (SGs) and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau. Imaging and immunoprecipitation verify the HNRNPA2B1 association with endogenous oTau in neurons, animal models and human Alzheimer brain tissue. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N6-methyladenosine modified transcripts (m6A). Knockdown of HNRNPA2B1 prevents oTau from associating with m6A, prevents oTau-induced reductions in protein synthesis and reduces oTau-induced toxicity. Finally, we show striking increases in m6A-oTau and -HNRNPA2B1 complexes in brains of Alzheimer subjects and P301S tau mice. These results reveal a novel complex containing oTau, HNRNPA2B1 and m6A that contributes to the integrated stress response of oTau.HighlightsDevelopment of a powerful method combining optical induction of tau oligomerization with precision mass spectrometry to obtain time resolved evolution of protein interaction networks.Demonstration of a tripartite complex that links tau oligomers with HNRNPA2B1 and N6-methyladenosine modified RNA in cytoplasmic stress granules.Knockdown of HNRNPA2B 1 abrogates the interactions of oTau with N6-methyladenosine modified RNA, as well as inhibits oTau-mediated neurodegeneration.Discovery that N6-methyladenosine modified RNA is significantly increased in the brains of P301S tau transgenic mice and in patients with Alzheimer’s disease.