Nicotinamide mononucleotide adenylyltransferase uses its NAD+ substrate-binding site to chaperone phosphorylated Tau.
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Abstract
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.
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Funder: Science and Technology Commission of Shanghai Municipality; FundRef: http://dx.doi.org/10.13039/501100003399
Funder: Dr. John T. MacDonald Foundation; FundRef: http://dx.doi.org/10.13039/100010239
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2050-084X
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Major State Basic Research Development Program (2016YFA0501902)
University of Miami (Lois Pope LIFE fellows Program)
National Institutes of Health (R56NS095893)
National Institutes of Health (R61AT010408)
Shanghai Pujiang Program (18PJ1404300)
Shanghai Municipal Science and Technology Major Project (2019SHZDZX02)
Shanghai Municipal Education Commission (Innovation Program 2019-01-07-00-02-E00037)
Shanghai Municipal Education Commission (“Eastern Scholar” project)