NAD and axon degeneration: From the Wlds gene to neurochemistry

Wang, Jing; He, Zhigang

doi:10.4161/cam.3.1.7483

Cited by 45 publications

(35 citation statements)

References 94 publications

(122 reference statements)

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“…Although NMNAT activity is increased, the cellular NAD concentration remains unchanged (21,22). Therefore, the delay in axon degeneration following nerve transection in Wld S mice may, at least in part, result from non-catalytic functions of NMNAT1, although the exact mechanism is still controversial (20,(23)(24)(25)(26). * This work was supported by the National Research Council of Norway and Human NMNAT2 was localized to the Golgi complex, whereas NMNAT3 is a mitochondrial protein (27,28).…”

Section: A-c)mentioning

confidence: 99%

Isoform-specific Targeting and Interaction Domains in Human Nicotinamide Mononucleotide Adenylyltransferases

Lau

Dölle

Gossmann

et al. 2010

Journal of Biological Chemistry

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Several important signaling pathways require NAD as substrate, thereby leading to significant consumption of the molecule. Because NAD is also an essential redox carrier, its continuous resynthesis is vital. In higher eukaryotes, maintenance of compartmentalized NAD pools is critical, but so far rather little is known about the regulation and subcellular distribution of NAD biosynthetic enzymes. The key step in NAD biosynthesis is the formation of the dinucleotide by nicotinamide/nicotinic acid mononucleotide adenylyltransferases (NMNATs). The three human isoforms were localized to the nucleus, the Golgi complex, and mitochondria. Here, we show that their genes contain unique exons that encode isoform-specific domains to mediate subcellular targeting and post-translational modifications. These domains are dispensable for catalytic activity, consistent with their absence from NMNATs of lower organisms. We further demonstrate that the Golgi-associated NMNAT is palmitoylated at two adjacent cysteine residues of its isoformspecific domain and thereby anchored at the cytoplasmic surface, a potential mechanism to regulate the cytosolic NAD pool. Insertion of unique domains thus provides a yet unrecognized enzyme targeting mode, which has also been adapted to modulate subcellular NAD supply.The metabolism of NAD has emerged as a complex network of reactions with immediate impact on fundamental biological processes (1-3). Even though the vital importance of this molecule has long been recognized, the molecular mechanisms of its synthesis and their regulation have moved into focus only in recent years. Although the bioenergetic role of NAD in reversible electron transfer reactions has been known for decades, only now has it become clear that this nucleotide is also a versatile component of signal transduction pathways, in which it is permanently degraded (1-3). For example, PARP1 (poly(ADPribose) polymerase-1) mediates DNA repair and cell stress responses (4 -6); NAD-dependent protein deacetylases, sirtuins, are involved in metabolic and life span regulation (7-10); and ADP-ribosyl cyclases use NAD to generate second messengers mediating calcium signaling (2,11,12). Because of the ongoing degradation in these reactions, continuous resynthesis of NAD is vital.Although the molecular details of NAD synthesis are still far from being understood, the central role of nicotinamide mononucleotide adenylyltransferases (NMNATs) 2 has been established (13-16). These enzymes catalyze the reaction at which all NAD biosynthetic pathways merge, the formation of the dinucleotide from NMN (or the nicotinic acid derivative, nicotinic acid mononucleotide) and ATP. Most NMNATs are homooligomers composed of ϳ30-kDa subunits. In mammals, there are three compartment-specific isoforms that likely maintain independent subcellular NAD pools.Three-dimensional structures of several NMNATs, including human isoforms 1 and 3, have been established (reviewed in Refs. 13 and 16). Interestingly, the subunit structures of both human NMNAT1 and NMNAT3 cont...

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Section: A-c)mentioning

confidence: 99%

Isoform-specific Targeting and Interaction Domains in Human Nicotinamide Mononucleotide Adenylyltransferases

Lau

Dölle

Gossmann

et al. 2010

Journal of Biological Chemistry

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“…[26][27][28][29][30] Considering the multifaceted roles NAD + has in maintaining cellular homeostasis, it is predictable that perturbations that affect NAD + levels and/or distribution would lead to various diseases, including cancer. Additionally, recent evidence that NAD + regulates p53 stability and activities via SIRTs while being back regulated by p53 via a feedback loop further attests to the intimate relationship between NAD + metabolism and cancer control.…”

Section: Nadmentioning

confidence: 99%

The NAD+ salvage pathway modulates cancer cell viability via p73

et al. 2015

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The involvement of the nicotinamide adenine dinucleotide (NAD + ) salvage pathway in cancer cell survival is poorly understood. Here we show that the NAD + salvage pathway modulates cancer cell survival through the rarely mutated tumour suppressor p73. Our data show that pharmacological inhibition or knockdown of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD + salvage pathway, enhances autophagy and decreases survival of cancer cells in a p53-independent manner. Such NAMPT inhibition stabilizes p73 independently of p53 through increased acetylation and decreased ubiquitination, resulting in enhanced autophagy and cell death. These effects of NAMPT inhibition can be effectively reversed using nicotinamide mononucleotide (NMN), the enzymatic product of NAMPT. Similarly, knockdown of p73 also decreases NAMPT inhibition-induced autophagy and cell death, whereas overexpression of p73 alone enhances these effects. We show that the breast cancer cell lines (MCF-7, MDA-MB-231 and MDA-MB-468) harbour significantly higher levels of NAMPT and lower levels of p73 than does the normal cell line (MCF-10A), and that NAMPT inhibition is cytotoxic exclusively to the cancer cells. Furthermore, data from 176 breast cancer patients demonstrate that higher levels of NAMPT and lower levels of p73 correlate with poorer patient survival, and that high-grade tumours have significantly higher NAMPT/p73 mRNA ratios. Therefore, the inverse relationship between NAMPT and p73 demonstrable in vitro is also reflected from the clinical data. Taken together, our studies reveal a new NAMPT-p73 nexus that likely has important implications for cancer diagnosis, prognosis and treatment.

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“…al. 2014 for an extensive summary of the effects of Wld S /NMNAT on various axon pathologies [47]) [48–50]. Study of the Wld S protein and its constituents has provided great insight into mechanisms of axonal viability that rely on the interrelated processes of metabolic homeostasis, calcium buffering, axonal transport, and protein synthesis.…”

Section: Lifelong Axon Maintenancementioning

confidence: 99%

“…Axons require large amounts of energy and metabolites to support membrane depolarization and synaptic transmission [51], and thus the NAD + biosynthetic NMNAT enzymes are essential in axon maintenance [48–50]. Mammalian NMNAT isoforms include the nuclear NMNAT1, the golgi-associated NMNAT2, and the mitochondrial NMNAT3 [50].…”

Section: Lifelong Axon Maintenancementioning

confidence: 99%

Preserve and protect: maintaining axons within functional circuits

Pease

Segal

2014

Trends in Neurosciences

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During development, neural circuits are initially generated by exuberant innervation and are rapidly refined by selective preservation and elimination of axons. The establishment and maintenance of functional circuits therefore requires coordination of axon survival and degeneration pathways. Both developing and mature circuits rely on interdependent mitochondrial and cytoskeletal components to maintain axonal health and homeostasis; injury or diseases that impinge on these components frequently cause pathologic axon loss. Here, we review recent findings that identify mechanisms of axonal preservation in the contexts of development, injury, and disease.

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NAD and axon degeneration: From the Wlds gene to neurochemistry

Cited by 45 publications

References 94 publications

Isoform-specific Targeting and Interaction Domains in Human Nicotinamide Mononucleotide Adenylyltransferases

Isoform-specific Targeting and Interaction Domains in Human Nicotinamide Mononucleotide Adenylyltransferases

The NAD+ salvage pathway modulates cancer cell viability via p73

Preserve and protect: maintaining axons within functional circuits

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