期刊
MOLECULAR CELL
卷 81, 期 20, 页码 4209-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2021.07.038
关键词
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资金
- Alzheimer Disease Centers (ADC) of Boston University (NIH) [AG50204517, P30-AG13846]
- Emory University [P30 AG066511]
- NIH [AG050471, NS089544, AG056318, AG064932, AG061706]
- BrightFocus Foundation
The study found that oTau-c induces tau phosphorylation, aggregation, and a translational stress response, and identified HNRNPA2B1 as a principle target of oTau-c. HNRNPA2B1 functions as a linker connecting oTau with N6-methyladenosine (m6A) modified RNA transcripts.
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,
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