@article{cb5e4996921a481e9ee84f889b0889c8,
title = "Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy",
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",
author = "Lulu Jiang and Weiwei Lin and Cheng Zhang and Ash, {Peter E.A.} and Mamta Verma and Julian Kwan and {van Vliet}, Emily and Zhuo Yang and Cruz, {Anna Lourdes} and Samantha Boudeau and Maziuk, {Brandon F.} and Shuwen Lei and Jaehyup Song and Alvarez, {Victor E.} and Stacy Hovde and Abisambra, {Jose F.} and Kuo, {Min Hao} and Nicholas Kanaan and Murray, {Melissa E.} and Crary, {John F.} and Jian Zhao and Cheng, {Ji Xin} and Leonard Petrucelli and Hu Li and Andrew Emili and Benjamin Wolozin",
note = "Funding Information: We thank Cliff Brangwynne and David Sanders (Princeton) for the Cry2Oligo constructs, Peter Davies (Northwell/Hofstra) for the tau13 antibody, and Philip Dolan (Prothena) for the 12E8 antibody. Brain tissues were provided by the Alzheimer Disease Centers (ADC) of Boston University (NIH grants AG50204517 and P30-AG13846), Emory University (P30 AG066511), the Mayo Clinic, and Mount Sinai Medical Center. We would like to thank the following funding agencies for their support: to B.W. NIH (AG050471, NS089544, AG056318, AG064932, AG061706) and the BrightFocus Foundation. Conceptualization, B.W. and L.J.; Methodology, L.J. W.L. P.E.A.A. C.Z. J.K. M.V. S.B. B.F.M. S.L. A.L.C. J.F.A. and E.V.V.; Investigation, L.J. W.L. M.V. P.E.A. and E.V.V.; Reagents, L.P. N.K. M.E.M. J.F.C. V.E.A. S.H. and M.-H.K.; Visualization, L.J. C.Z. H.L. W.L. J.S. J.Z. and J.-X.C.; Writing, L.J. and B.W.; Editing, B.W. L.J. A.E. W.L. L.P. N.K. and P.E.A.A.; Supervision, B.W. and A.E.; Funding Acquisition, B.W. and A.E. B.W. is a co-founder and chief scientific officer of Aquinnah Pharmaceuticals Inc. Funding Information: We thank Cliff Brangwynne and David Sanders (Princeton) for the Cry2Oligo constructs, Peter Davies (Northwell/Hofstra) for the tau13 antibody, and Philip Dolan (Prothena) for the 12E8 antibody. Brain tissues were provided by the Alzheimer Disease Centers (ADC) of Boston University ( NIH grants AG50204517 and P30-AG13846 ), Emory University ( P30 AG066511 ), the Mayo Clinic, and Mount Sinai Medical Center. We would like to thank the following funding agencies for their support: to B.W., NIH ( AG050471 , NS089544 , AG056318 , AG064932 , AG061706 ) and the BrightFocus Foundation . Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = oct,
day = "21",
doi = "10.1016/j.molcel.2021.07.038",
language = "English",
volume = "81",
pages = "4209--4227.e12",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "20",
}