TY - JOUR TI - Nicotinamide mononucleotide adenylyltransferase uses its NAD+ substrate-binding site to chaperone phosphorylated Tau AU - Ma, Xiaojuan AU - Zhu, Yi AU - Lu, Jinxia AU - Xie, Jingfei AU - Li, Chong AU - Shin, Woo Shik AU - Qiang, Jiali AU - Liu, Jiaqi AU - Dou, Shuai AU - Xiao, Yi AU - Wang, Chuchu AU - Jia, Chunyu AU - Long, Houfang AU - Yang, Juntao AU - Fang, Yanshan AU - Jiang, Lin AU - Zhang, Yaoyang AU - Zhang, Shengnan AU - Zhai, Rong Grace AU - Liu, Cong AU - Li, Dan A2 - Goedert, Michel A2 - Ron, David A2 - Lu, Hui-Chen A2 - Bieschke, Jan A2 - Lasmezas, Corinne VL - 9 PY - 2020 DA - 2020/04/06 SP - e51859 C1 - eLife 2020;9:e51859 DO - 10.7554/eLife.51859 UR - https://doi.org/10.7554/eLife.51859 AB - Tau hyper-phosphorylation and deposition into neurofibrillary tangles have been found in brains of patients with Alzheimer’s disease (AD) and other tauopathies. Molecular chaperones are involved in regulating the pathological aggregation of phosphorylated Tau (pTau) and modulating disease progression. Here, we report that nicotinamide mononucleotide adenylyltransferase (NMNAT), a well-known NAD+ synthase, serves as a chaperone of pTau to prevent its amyloid aggregation in vitro as well as mitigate its pathology in a fly tauopathy model. By combining NMR spectroscopy, crystallography, single-molecule and computational approaches, we revealed that NMNAT adopts its enzymatic pocket to specifically bind the phosphorylated sites of pTau, which can be competitively disrupted by the enzymatic substrates of NMNAT. Moreover, we found that NMNAT serves as a co-chaperone of Hsp90 for the specific recognition of pTau over Tau. Our work uncovers a dedicated chaperone of pTau and suggests NMNAT as a key node between NAD+ metabolism and Tau homeostasis in aging and neurodegeneration. KW - Alzheimer's disease KW - tauopathy KW - phosphorylated Tau KW - chaperone KW - NMNAT KW - NAD synthase JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -