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

• DOI: 10.1016/j.molcel.2021.07.038
• Publication Date: 2021-08-27T14:38:03Z
• Authors: 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. Crary; Jian Zhao; Ji-Xin Cheng; Leonard Petrucelli; Hu Li; Andrew Emili; Benjamin Wolozin
• Keywords: Tauopathy; Stress granule; Linker

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.