NMNAT2: An important metabolic enzyme affecting the disease progression

Li, Wentao; Gao, Mengxiang; Hu, Chunhui; Chen, Xiuwen; Zhou, Yanhong

doi:10.1016/j.biopha.2022.114143

Cited by 9 publications

(3 citation statements)

References 99 publications

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“…Axons require the axonal NAD-synthesizing enzyme NMNAT2 to survive [20,37]. NMNAT2 is reduced in the brains of Alzheimer's and other neurodegenerative diseases [38]. In cortical neurons, knockdown of NMNAT1 results in a significant decrease in axon growth and branching [39].…”

Section: Effect Of Nad Precursors On Neurite Growthmentioning

confidence: 99%

NAD+ Precursors Reverse Experimental Diabetic Neuropathy in Mice

Chandrasekaran,

Najimi,

Sagi

et al. 2024

IJMS

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Abnormal NAD+ signaling has been implicated in axonal degeneration in diabetic peripheral neuropathy (DPN). We hypothesized that supplementing NAD+ precursors could alleviate DPN symptoms through increasing the NAD+ levels and activating the sirtuin-1 (SIRT1) protein. To test this, we exposed cultured Dorsal Root Ganglion neurons (DRGs) to Nicotinamide Riboside (NR) or Nicotinamide Mononucleotide (NMN), which increased the levels of NAD+, the SIRT1 protein, and the deacetylation activity that is associated with increased neurite growth. A SIRT1 inhibitor blocked the neurite growth induced via NR or NMN. We then induced neuropathy in C57BL6 mice with streptozotocin (STZ) or a high fat diet (HFD) and administered NR or NMN for two months. Both the STZ and HFD mice developed neuropathy, which was reversed through the NR or NMN administration: sensory function improved, nerve conduction velocities normalized, and intraepidermal nerve fibers were restored. The NAD+ levels and SIRT1 activity were reduced in the DRGs from diabetic mice but were preserved with the NR or NMN treatment. We also tested the effect of NR or NMN administration in mice that overexpress the SIRT1 protein in neurons (nSIRT1 OE) and found no additional benefit from the addition of the drug. These findings suggest that supplementing with NAD+ precursors or activating SIRT1 may be a promising treatment for DPN.

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Section: Effect Of Nad Precursors On Neurite Growthmentioning

confidence: 99%

NAD+ Precursors Reverse Experimental Diabetic Neuropathy in Mice

Chandrasekaran,

Najimi,

Sagi

et al. 2024

IJMS

View full text Add to dashboard Cite

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“…Similar to NMNAT1, NMNAT2 is also a recognized neuroprotective factor that plays an essential role in maintaining axonal integrity through its NAD + synthetase catalytic activity as well as by acting as a molecular chaperone [131]. The suppression of NM-NAT2 skews the homeostatic balance that is maintained by the NMNAT2-NAD + -SARM1 axis and results in axonal degeneration, an effect that is commonly observed in many neurodegenerative diseases or as a physiological response to nerve injury (Wallerian degeneration) [131,132]. NMNAT2 also protects against chemotherapy-induced peripheral neuropathy [131].…”

Section: Nmnat As a Target In Cancermentioning

confidence: 99%

“…The suppression of NM-NAT2 skews the homeostatic balance that is maintained by the NMNAT2-NAD + -SARM1 axis and results in axonal degeneration, an effect that is commonly observed in many neurodegenerative diseases or as a physiological response to nerve injury (Wallerian degeneration) [131,132]. NMNAT2 also protects against chemotherapy-induced peripheral neuropathy [131]. A recent study illustrated that peripheral neuropathy caused by the chemotherapeutic agents vincristine and bortezomib is also triggered through axonal NMNAT2 depletion and that the consequent NAD + loss is induced through SARM1 activation [133].…”

Section: Nmnat As a Target In Cancermentioning

confidence: 99%

Inhibitors of NAD+ Production in Cancer Treatment: State of the Art and Perspectives

Ghanem,

Caffa,

Monacelli

et al. 2024

IJMS

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The addiction of tumors to elevated nicotinamide adenine dinucleotide (NAD+) levels is a hallmark of cancer metabolism. Obstructing NAD+ biosynthesis in tumors is a new and promising antineoplastic strategy. Inhibitors developed against nicotinamide phosphoribosyltransferase (NAMPT), the main enzyme in NAD+ production from nicotinamide, elicited robust anticancer activity in preclinical models but not in patients, implying that other NAD+-biosynthetic pathways are also active in tumors and provide sufficient NAD+ amounts despite NAMPT obstruction. Recent studies show that NAD+ biosynthesis through the so-called “Preiss-Handler (PH) pathway”, which utilizes nicotinate as a precursor, actively operates in many tumors and accounts for tumor resistance to NAMPT inhibitors. The PH pathway consists of three sequential enzymatic steps that are catalyzed by nicotinate phosphoribosyltransferase (NAPRT), nicotinamide mononucleotide adenylyltransferases (NMNATs), and NAD+ synthetase (NADSYN1). Here, we focus on these enzymes as emerging targets in cancer drug discovery, summarizing their reported inhibitors and describing their current or potential exploitation as anticancer agents. Finally, we also focus on additional NAD+-producing enzymes acting in alternative NAD+-producing routes that could also be relevant in tumors and thus become viable targets for drug discovery.

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