Nicotinamide mononucleotide adenylyltransferase uses its NAD+ substrate-binding site to chaperone phosphorylated Tau

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.

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

“…513 NMNAT, as a binding partner of HSP90, can specifically recognize p-Tau to inhibit its amyloid aggregation in vitro and reduce its symptoms in the fly tauopathy model, and this effect could be competitively destroyed by its enzymatic substrate. 514 Parkinson's disease (PD). PD is a common neurodegenerative disease, mainly including motor and non-motor symptoms.…”

Uncovering the Invisible: Mono-ADP-ribosylation Moved into the Spotlight

“…Recent studies have now challenged the well-established role of NMNAT-catalyzed NAD + production and might provide explanations for the above-described discrepancies between in vitro and in vivo studies. Those reports propose that NMNATs additionally exert important chaperone functions that are critical for neuronal health [ 51 , 52 , 53 ]. To which extent this potential chaperone function has to be taken into consideration for experiments in cell culture has to further be assessed by including NMNAT mutants that can discriminate between the two functions.…”

Tau-mediated axonal degeneration is prevented by activation of the WldSpathway

“…Nonetheless it is possible that this protective effect was conferred by reduced misfolding or phosphorylation at other pathological sites that have previously been implicated in tau-mediated degeneration in other Drosophila models of tauopathy, such as MC1 (57), AT100 (Thr212/Ser214) (58) or 12E8 (ser262/356) (35) or reduced aggregation of human tau remains to be determined by future studies. It is conceivable that Wld S pathway activation may influence tau phosphorylation at other sites as well as modulate tau aggregation, as several isoforms of NMNAT, one of which is a component of Wld S fusion protein, have been shown to act as potent chaperones of phosphorylated tau, preventing its aggregation in vitro (37). This report, and others like it which implicate NMNAT in modulation of taumediated toxicity in other experimental models (38) (39), suggest that activation of Wld S pathway does not act downstream of tau, and instead there are some key points of intersection.…”