NMNAT2

What is NMNAT2 protein?

NMNAT2 (nicotinamide nucleotide adenylyltransferase 2) gene is a protein coding gene which situated on the long arm of chromosome 1 at locus 1q25. This gene product belongs to the nicotinamide mononucleotide adenylyltransferase (NMNAT) enzyme family, members of which catalyze an essential step in NAD (NADP) biosynthetic pathway. Unlike the other human family member, which is localized to the nucleus, and is ubiquitously expressed; this enzyme is cytoplasmic, and is predominantly expressed in the brain. Two transcript variants encoding different isoforms have been found for this gene. The NMNAT2 protein is consisted of 307 amino acids and its molecular mass is approximately 34.4 kDa.

What is the function of NMNAT2 protein?

NMNAT2 has been shown to have a neuroprotective function. It is involved in maintaining the health of neurons and is particularly important for axonal survival. The enzyme is a critical survival factor for axons, and its levels can influence the activation of SARM1, a protein involved in axonal degeneration. NMNAT2 is an NAD+ synthase, meaning it is involved in the synthesis of nicotinamide adenine dinucleotide (NAD+), which is a vital coenzyme for numerous cellular redox reactions and signaling pathways, including DNA repair and cell differentiation. NMNAT2 has a molecular chaperone function that is independent of its enzymatic activity. NMNAT2 supports axonal maintenance, which is crucial for the proper functioning of neurons.

NMNAT2 Related Signaling Pathway

NMNAT2-NAD+-SARM1 Signal Pathway is closely related to axonal degeneration, a process known as Wallerian degeneration. When NMNAT2 levels decrease due to physical injury or pathological stimulation, it leads to the activation of SARM1, which in turn causes axonal degeneration. This process is associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and peripheral neuropathy. NMNAT2 is a key enzyme in the NAD+ salvage pathway, which is essential for maintaining NAD+ levels in the cell. This pathway is particularly important in the context of aging and age-related diseases, as NAD+ levels decline with age.

Fig1. Mechanism of SARM1 activation by the NMNAT2-NAD+-SARM1 signaling axis. (Wentao Li, 2023)

NMNAT2 Related Diseases

The NMNAT2 protein, or nicotinamide mononucleotide adenylyltransferase 2, is an enzyme that plays a critical role in several biological processes, particularly in the context of neurodegenerative diseases and cancer. NMNAT2 is implicated in the pathology of several diseases. Its decrease can lead to the activation of pathways that cause axonal degeneration, which is associated with conditions like amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and peripheral neuropathy. NMNAT2 also has a role in cancer, where it can promote the occurrence and development of solid tumors, including colorectal, lung, ovarian, and glioma.

Bioapplications of NMNAT2

Given its role in maintaining axonal health and its involvement in NAD+ synthesis, NMNAT2 is considered a potential therapeutic target for treating neurodegenerative diseases. Modulating its activity could help slow disease progression or improve symptoms. Since NAD+ levels decline with age, and this decline is associated with a decrease in the expression of NMNAT2, the enzyme is being studied in the context of aging and age-related diseases.

Case Study 1: Lu-Zhe Pan, 2014

NAD(+) metabolism plays key roles not only in energy production but also in diverse cellular physiology. Aberrant NAD(+) metabolism is considered a hallmark of cancer. Recently, the tumor suppressor p53, a major player in cancer signaling pathways, has been implicated as an important regulator of cellular metabolism. This notion led us to examine whether p53 can regulate NAD(+) biosynthesis in the cell. This search resulted in the identification of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2), a NAD(+) synthetase, as a novel downstream target gene of p53. The results show that NMNAT-2 expression is induced upon DNA damage in a p53-dependent manner. Two putative p53 binding sites were identified within the human NMNAT-2 gene, and both were found to be functional in a p53-dependent manner. Furthermore, knockdown of NMNAT-2 significantly reduces cellular NAD(+) levels and protects cells from p53-dependent cell death upon DNA damage, suggesting an important functional role of NMNAT-2 in p53-mediated signaling.

Fig1. Protein levels of p53 and NMNAT-2 were compared.

Fig2. The percentage of dead cells was determined by sub-G1 DNA content analysis using flow cytometry.

Case Study 2: Yousuf O Ali, 2016

Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is neuroprotective in numerous preclinical models of neurodegeneration. Here, the researchers show that brain nmnat2 mRNA levels correlate positively with global cognitive function and negatively with AD pathology. In AD brains, NMNAT2 mRNA and protein levels are reduced. NMNAT2 shifts its solubility and colocalizes with aggregated Tau in AD brains, similar to chaperones, which aid in the clearance or refolding of misfolded proteins. Investigating the mechanism of this observation, they discover a novel chaperone function of NMNAT2, independent from its enzymatic activity. NMNAT2 complexes with heat shock protein 90 (HSP90) to refold aggregated protein substrates. NMNAT2's refoldase activity requires a unique C-terminal ATP site, activated in the presence of HSP90. Furthermore, deleting NMNAT2 function increases the vulnerability of cortical neurons to proteotoxic stress and excitotoxicity. Interestingly, NMNAT2 acts as a chaperone to reduce proteotoxic stress, while its enzymatic activity protects neurons from excitotoxicity.

Fig3. NMNAT2 protein levels were reduced in the soluble fractions of AD brains.

Fig4. Summary of luciferase assay in NMNAT2-expressing cells with various treatments.

NMNAT2 has several biochemical functions, for example, ATP binding,nicotinamide-nucleotide adenylyltransferase activity,nicotinate-nucleotide adenylyltransferase activity. Some of the functions are cooperated with other proteins, some of the functions could acted by NMNAT2 itself. We selected most functions NMNAT2 had, and list some proteins which have the same functions with NMNAT2. You can find most of the proteins on our site.

NMNAT2 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with NMNAT2 here. Most of them are supplied by our site. Hope this information will be useful for your research of NMNAT2.