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.
Highlights
Phosphorylated Tau is the major component of the neurofibrillary tangles that are commonly found in the brains of patients with Alzheimer’s disease (AD) and many other tauopathy-relatedMa et al eLife 2020;9:e51859
The microtubule affinity regulating kinase 2 (MARK2) phosphorylation sites on Tau23 and K19 were characterized by 2D 1H-15N Nuclear magnetic resonance (NMR) HSQC spectra (Figure 1A; Figure 1—figure supplement 1)
To assess the functional relevance of the direct regulation of nicotinamide mononucleotide adenylyltransferase (NMNAT) on the abnormal aggregation of Phosphorylated Tau (pTau) in vivo, we examined the protective capability of Nmnat in Drosophila tauopathy models by overexpressing human wild type (TauWT) or pathogenic Tau (TauR406W) in the visual system using a photoreceptor-specific driver GMR-GAL4 (Ali et al, 2012)
Summary
Phosphorylated Tau (pTau) is the major component of the neurofibrillary tangles that are commonly found in the brains of patients with Alzheimer’s disease (AD) and many other tauopathy-related. In addition to the well-studied NAD+ synthase activity, NMNAT has been found to be able to retrieve the activity of luciferase from heat-denatured amorphous aggregation suggesting a chaperone-like activity of NMNAT (Ali et al, 2016; Zhai et al, 2008). It remains puzzling how a single domain enzyme, that has no similarity to any known chaperones, fulfills a chaperone-like activity. Our work suggests an interplay of NAD+ metabolism and the progression of Tau pathology in aging and neurodegeneration
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