NMNAT: It's an NAD+ synthase… It's a chaperone… It's a neuroprotector

Abstract

Nicotinamide mononucleotide adenylyl transferases (NMNATs) are a family of highly conserved proteins indispensable for cellular homeostasis. NMNATs are classically known for their enzymatic function of catalyzing NAD⁺ synthesis, but also have gained a reputation as essential neuronal maintenance factors. NMNAT deficiency has been associated with various human diseases with pronounced consequences on neural tissues, underscoring the importance of the neuronal maintenance and protective roles of these proteins. New mechanistic studies have challenged the role of NMNAT-catalyzed NAD⁺ production in delaying Wallerian degeneration and have specified new mechanisms of NMNAT's chaperone function critical for neuronal health. Progress in understanding the regulation of NMNAT has uncovered a neuronal stress response with great therapeutic promise for treating various neurodegenerative conditions.

Figure 1. Genetic and transcriptional alterations of NMNATs in human diseases

Mutations across human NMNAT1 gene cause LCA9, characterized by early-onset and rapid progression of vision loss and retinal degeneration. Decreased mRNA levels of human NMNAT2 and NMNAT3 are correlated with cognitive dysfunction and neurodegeneration. In both conditions, the NMNAT protein stability or levels are decreased affecting their enzyme activity and/or molecular chaperone capacity and comprising the neuroprotective function.

Figure 2. Regulation of NMNAT in neurons

Under stress conditions, binding of transcription factors to the NMNAT promoter region induces transcription as a neuronal self-protective mechanism. Under pathological conditions, binding of transcription factors to the promoter region is reduced, which leads to decreased NMNAT protein levels and exacerbates neurodegeneration. Constitutive proteasomal degradation of neuroprotective NMNAT is regulated by an atypical ligase complex comprising Skp1a, Phr1, and Fbxo45. Potential therapeutic targets include maintaining or enhancing NMNAT transcription (1) and suppressing NMNAT degradation (2) to combat neurodegeneration in a wide variety of settings.

Figure 3. Transcriptional regulation of Drosophila Nmnat under stress

Under heat shock or hypoxic stress, Drosophila Nmnat transcription is upregulated directly through heat shock factor (HSF) or indirectly through hypoxia-inducible factor-1α (HIF-1α). Proteotoxic stress (in models of proteinopathy, such as tauopathy and spinocerebellar ataxia) also induces transcriptional upregulation of Drosophila Nmnat, although the mechanism remains to be determined. In neurons, the splicing of Nmnat pre-mRNA is switched to Nmnat-RB under stress conditions to promote the production of Nmnat-PD, therefore achieving neuronal protection (Figure modified from [43]).