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Jennifer M Brazill, Chong Li, Yi Zhu, R Grace Zhai
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...
April 23, 2017: Current Opinion in Genetics & Development
Meredith E Jackrel, James Shorter
Protein misfolding is implicated in numerous neurodegenerative disorders including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease. A unifying feature of patients with these disorders is the accumulation of deposits comprised of misfolded protein. Aberrant protein folding can cause toxicity through a loss or gain of protein function, or both. An intriguing therapeutic approach to counter these disorders is the application of protein-remodeling factors to resolve these misfolded conformers and return the proteins to their native fold and function...
2017: Frontiers in Neuroscience
Michele Di Stefano, Andrea Loreto, Giuseppe Orsomando, Valerio Mori, Federica Zamporlini, Richard P Hulse, Jamie Webster, Lucy F Donaldson, Martin Gering, Nadia Raffaelli, Michael P Coleman, Jonathan Gilley, Laura Conforti
Axons require the axonal NAD-synthesizing enzyme NMNAT2 to survive. Injury or genetically induced depletion of NMNAT2 triggers axonal degeneration or defective axon growth. We have previously proposed that axonal NMNAT2 primarily promotes axon survival by maintaining low levels of its substrate NMN rather than generating NAD; however, this is still debated. NMN deamidase, a bacterial enzyme, shares NMN-consuming activity with NMNAT2, but not NAD-synthesizing activity, and it delays axon degeneration in primary neuronal cultures...
March 20, 2017: Current Biology: CB
Li Chen, Derek M Nye, Michelle C Stone, Alexis T Weiner, Kyle W Gheres, Xin Xiong, Catherine A Collins, Melissa M Rolls
Axon injury can lead to several cell survival responses including increased stability and axon regeneration. Using an accessible Drosophila model system, we investigated the regulation of injury responses and their relationship. Axon injury stabilizes the rest of the cell, including the entire dendrite arbor. After axon injury we found mitochondrial fission in dendrites was upregulated, and that reducing fission increased stabilization or neuroprotection (NP). Thus axon injury seems to both turn on NP, but also dampen it by activating mitochondrial fission...
December 2016: PLoS Genetics
Seiichi Tanuma, Akira Sato, Takahiro Oyama, Atsushi Yoshimori, Hideaki Abe, Fumiaki Uchiumi
Accumulating evidence has suggested the fundamental functions of NAD+-poly(ADP-ribose) metabolism in cellular and physiological processes, including energy homeostasis, signal transduction, DNA transaction, genomic stability and cell death or survival. The NAD+ biosynthesis and poly(ADP-ribose) [(ADP-R)n] turnover are tightly controlled by several key enzymes, such as nicotinamide phosphoribosyltransferase (NmPRT), nicotinamide mononucleotide adenylyltransferases (NMNATs), poly(ADP-ribose) polymerase (PARP), poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribose pyrophosphorylase (ADPRPPL)...
2016: Current Protein & Peptide Science
Diana Milena Sánchez-Lancheros, Luis Fernando Ospina-Giraldo, María Helena Ramírez-Hernández
Nicotinamide/nicotinate adenine dinucleotide (NAD+/NaAD) performs essential functions in cell metabolism and energy production due to its redox properties. The nicotinamide/nicotinate mononucleotide adenylyltransferase (NMNAT, EC enzyme catalyses the key step in the biosynthesis of NAD+. Previously, the enzyme NMNAT was identified in Trypanosoma cruzi (TcNMNAT), a pathogenic agent with epidemiological importance in Latin America. To continue with the functional characterisation of this enzyme, its subcellular location and its possible post-translational modifications were examined in this study...
November 2016: Memórias do Instituto Oswaldo Cruz
Erik S Musiek, David D Xiong, Tirth Patel, Yo Sasaki, Yinong Wang, Adam Q Bauer, Risham Singh, Samantha L Finn, Joseph P Culver, Jeffrey Milbrandt, David M Holtzman
OBJECTIVE: The nicotinamide-nucleotide adenylyltransferase protein Nmnat1 is a potent inhibitor of axonal degeneration in models of acute axonal injury. Hyperphosphorylation and aggregation of the microtubule-associated protein Tau are associated with neurodegeneration in Alzheimer's Disease and other disorders. Previous studies have demonstrated that other Nmnat isoforms can act both as axonoprotective agents and have protein chaperone function, exerting protective effects in drosophila and mouse models of tauopathy...
June 2016: Annals of Clinical and Translational Neurology
Ji H Park, Aaron Long, Katrina Owens, Tibor Kristian
Nicotinamide adenine dinucleotide (NAD(+)) is an essential cofactor for multiple cellular metabolic reactions and has a central role in energy production. Brain ischemia depletes NAD(+) pools leading to bioenergetics failure and cell death. Nicotinamide mononucleotide (NMN) is utilized by the NAD(+) salvage pathway enzyme, nicotinamide adenylyltransferase (Nmnat) to generate NAD(+). Therefore, we examined whether NMN could protect against ischemic brain damage. Mice were subjected to transient forebrain ischemia and treated with NMN or vehicle at the start of reperfusion or 30min after the ischemic insult...
November 2016: Neurobiology of Disease
Chunhui Cui, Jia Qi, Quanwen Deng, Rihong Chen, Duanyang Zhai, Jinlong Yu
Colorectal cancer (CRC) is one of the most common cancers all over the world. It is essential to search for more effective diagnostic and therapeutic methods for CRC. Abnormal nicotinamide adenine dinucleotide (NAD) metabolism has been considered as a characteristic of cancer cells. In this study, nicotinamide mononucleotide adenylyl transferases (NMNATs) as well as p53-mediated cancer signaling pathways were investigated in patients with colorectal cancer. The CRC tissues and adjacent normal tissues were obtained from 95 untreated colorectal cancer patients and were stained for expression of nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) and p53...
2016: BioMed Research International
Matthew J Geden, Mohanish Deshmukh
Axon degeneration is an essential part of development, plasticity, and injury response and has been primarily studied in mammalian models in three contexts: 1) Axotomy-induced Wallerian degeneration, 2) Apoptosis-induced axon degeneration (axon apoptosis), and 3) Axon pruning. These three contexts dictate engagement of distinct pathways for axon degeneration. Recent advances have identified the importance of SARM1, NMNATs, NAD+ depletion, and MAPK signaling in axotomy-induced Wallerian degeneration. Interestingly, apoptosis-induced axon degeneration and axon pruning have many shared mechanisms both in signaling (e...
August 2016: Current Opinion in Neurobiology
Rong-Mei Zhou, Yi Shen, Jin Yao, Hong Yang, Kun Shan, Xiu-Miao Li, Qin Jiang, Biao Yan
BACKGROUND/AIMS: Retinal neurodegeneration is an early event in the pathological process of diabetic retinopathy (DR). Retinal ganglion cell (RGC) injury is an important pathological feature during neurodegenerative process. Protecting RGCs from high glucose-induced injury is a promising strategy for delaying or hindering diabetes mellitus-related retinal neuropathy. This study aims to investigate the role of Nmnat1, an enzyme which catalyzes a key step in the biosynthesis of nicotinamide adenine dinucleotide (NAD), in high glucose-induced RGC injury...
2016: Cellular Physiology and Biochemistry
Jyothi Padiadpu, Madhulika Mishra, Eshita Sharma, Uchurappa Mala, Kumar Somasundaram, Nagasuma Chandra
The biosynthesis of NAD constitutes an important metabolic module in the cell, since NAD is an essential cofactor involved in several metabolic reactions. NAD concentrations are known to be significantly increased in several cancers, particularly in glioma, consistent with the observation of up-regulation of several enzymes of the network. Modulating NAD biosynthesis in glioma is therefore an attractive therapeutic strategy. Here we report reconstruction of a biochemical network of NAD biosynthesis consisting of 22 proteins, 36 metabolites, and 86 parameters, tuned to mimic the conditions in glioma...
May 23, 2016: Journal of Chemical Information and Modeling
Annika L A Nichols, Ellen Meelkop, Casey Linton, Rosina Giordano-Santini, Robert K Sullivan, Alessandra Donato, Cara Nolan, David H Hall, Ding Xue, Brent Neumann, Massimo A Hilliard
Axonal degeneration is a characteristic feature of neurodegenerative disease and nerve injury. Here, we characterize axonal degeneration in Caenorhabditis elegans neurons following laser-induced axotomy. We show that this process proceeds independently of the WLD(S) and Nmnat pathway and requires the axonal clearance machinery that includes the conserved transmembrane receptor CED-1/Draper, the adaptor protein CED-6, the guanine nucleotide exchange factor complex Crk/Mbc/dCed-12 (CED-2/CED-5/CED-12), and the small GTPase Rac1 (CED-10)...
February 23, 2016: Cell Reports
Richard A Slivicki, Yousuf O Ali, Hui-Chen Lu, Andrea G Hohmann
Nicotinamide mononucleotide adenylyl transferases (NMNATs) are essential neuronal maintenance factors postulated to preserve neuronal function and protect against axonal degeneration in various neurodegenerative disease states. We used in vitro and in vivo approaches to assess the impact of NMNAT2 reduction on cellular and physiological functions induced by treatment with a vinca alkaloid (vincristine) and a taxane-based (paclitaxel) chemotherapeutic agent. NMNAT2 null (NMNAT2-/-) mutant mice die at birth and cannot be used to probe functions of NMNAT2 in adult animals...
2016: PloS One
Kai Ruan, Yi Zhu, Chong Li, Jennifer M Brazill, R Grace Zhai
Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved enzyme in the NAD synthetic pathway. It has also been identified as an effective and versatile neuroprotective factor. However, it remains unclear how healthy neurons regulate the dual functions of NMNAT and achieve self-protection under stress. Here we show that Drosophila Nmnat (DmNmnat) is alternatively spliced into two mRNA variants, RA and RB, which translate to protein isoforms with divergent neuroprotective capacities against spinocerebellar ataxia 1-induced neurodegeneration...
November 30, 2015: Nature Communications
Carlos H Niño, Nicolás Forero-Baena, Luis E Contreras, Diana Sánchez-Lancheros, Katherine Figarella, María H Ramírez
The intracellular parasite Trypanosoma cruzi is the aetiological agent of Chagas disease, a public health concern with an increasing incidence rate. This increase is due, among other reasons, to the parasite's drug resistance mechanisms, which require nicotinamide adenine dinucleotide (NAD+). Furthermore, this molecule is involved in metabolic and intracellular signalling processes necessary for the survival of T. cruzi throughout its life cycle. NAD+biosynthesis is performed by de novo and salvage pathways, which converge on the step that is catalysed by the enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT) (enzyme commission number: 2...
November 2015: Memórias do Instituto Oswaldo Cruz
Roland Pfoh, Emil F Pai, Vivian Saridakis
Nicotinamide mononucleotide adenylyltransferase (NMNAT) catalyzes the biosynthesis of NAD(+) and NaAD(+). The crystal structure of NMNAT from Methanobacterium thermoautotrophicum complexed with NAD(+) and SO4(2-) revealed the active-site residues involved in binding and catalysis. Site-directed mutagenesis was used to further characterize the roles played by several of these residues. Arg11 and Arg136 were implicated in binding the phosphate groups of the ATP substrate. Both of these residues were mutated to lysine individually...
October 2015: Acta Crystallographica. Section D, Biological Crystallography
Luis E Contreras, Rafik Neme, María H Ramírez
The progressive increase in Leishmania resistance to current control approaches prompts the need to develop therapeutic strategies based on comprehensive knowledge of the parasite's biology. The enzyme Nicotinamide Mononucleotide Adenylyltransferase (NMNAT, EC catalyzes the central step in nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, making it essential for the survival of all organisms. NAD(+) metabolism is related to the maintenance of several biochemical, cellular, and physiological processes; consequently, the characterization and analysis of the enzymes involved in its biosynthesis represent key steps in the development of control strategies...
November 2015: Protein Expression and Purification
Tian-Ying Xu, Sai-Long Zhang, Guo-Qiang Dong, Xin-Zhu Liu, Xia Wang, Xiao-Qun Lv, Qi-Jun Qian, Ruo-Yu Zhang, Chun-Quan Sheng, Chao-Yu Miao
Nicotinamide phosphoribosyltransferase (NAMPT) is a promising anticancer target. Using high throughput screening system targeting NAMPT, we obtained a potent NAMPT inhibitor MS0 (China Patent ZL201110447488.9) with excellent in vitro activity (IC50 = 9.87 ± 1.15 nM) and anti-proliferative activity against multiple human cancer cell lines including stem-like cancer cells. Structure-activity relationship studies yielded several highly effective analogues. These inhibitors specifically bound NAMPT, rather than downstream NMNAT...
2015: Scientific Reports
Yunsheng Wang, Deming Zhao, Bo Pan, Zhiqi Song, Syed Zahid Ali Shah, Xiaomin Yin, Xiangmei Zhou, Lifeng Yang
Axonal degeneration is a hallmark of many neurodegenerative disorders including transmissible spongiform encephalopathies (TSE). However, the full complement of axonal degeneration triggers is not fully understood. In an in vitro prion model, we observed that treatment of rat spinal neurons with the prion peptide, PrP106-126, activated death receptor 6 (DR6, also known as TNFRSF21), caspase-6, caspase-3, and induced axonal degeneration. Knockdown of DR6 by siRNA blocked caspase-6 and caspase-3 activation and axonal degeneration...
August 2015: Journal of Molecular Neuroscience: MN
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