{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNMNAT2 is an essential enzyme that catalyzes the conversion of nicotinamide mononucleotide (NMN) and ATP into nicotinamide adenine dinucleotide (NAD+), a reaction central to cellular metabolism. Biochemical studies have revealed that, unlike its nuclear and mitochondrial counterparts, NMNAT2 is predominantly localized to the Golgi complex and other membrane compartments—its association with membranes being mediated by palmitoylation. Furthermore, kinetic analyses and cloning studies have underscored that NMNAT2 possesses unique substrate specificities and isoform‐specific properties in comparison with NMNAT1, and its tissue distribution is notably enriched in the brain, heart, muscle, and even pancreatic islets. In addition, NMNAT2 expression may be modulated by factors such as p53 in response to DNA damage, emphasizing its regulated role in NAD homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its enzymatic role, NMNAT2 plays a critical neuroprotective role by supporting axon growth and survival. Its maintenance in axons prevents the initiation of Wallerian degeneration—a process implicated in a variety of neurodegenerative states—and experimental overexpression of NMNAT2 has been shown to rescue injured axons. Intriguingly, NMNAT2 also exhibits a noncanonical chaperone function: it complexes with proteins such as heat shock protein 90 (HSP90) to facilitate the refolding of misfolded proteins, including aggregated tau. This dual functionality is context-dependent, with its enzymatic activity guarding against excitotoxicity and its chaperone activity mitigating proteotoxic stress. Furthermore, regulatory pathways—including CREB-mediated transcription and ubiquitination via PHR protein complexes—modulate NMNAT2 stability and function, with deficiencies in NMNAT2 linked to impaired axon trafficking and neurodegeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_fs", "start_ref": "9", "end_ref": "15"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic and clinical studies further reinforce the importance of NMNAT2 in human health. Variations in the NMNAT2 gene have been associated with distinct neurological phenotypes, ranging from neurodevelopmental disorders and axonal neuropathies (including cases manifesting as polyneuropathy with erythromelalgia or fetal akinesia deformation sequence) to altered susceptibility in inflammatory conditions such as Kawasaki disease. In addition, genome-wide analyses implicate NMNAT2 in psychiatric and cognitive traits, and its expression has been examined in contexts as diverse as diabetic retinopathy, suggesting that perturbations in NMNAT2 function may contribute to wide-ranging pathologies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "19"}]}, {"type": "t", "text": ""}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Laura Conforti, Jonathan Gilley, Michael P Coleman "}, {"type": "b", "children": [{"type": "t", "text": "Wallerian degeneration: an emerging axon death pathway linking injury and disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Rev Neurosci (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nrn3680"}], "href": "https://doi.org/10.1038/nrn3680"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24840802"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24840802"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Felicitas Berger, Corinna Lau, Mathias Dahlmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M508660200"}], "href": "https://doi.org/10.1074/jbc.M508660200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16118205"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16118205"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Nadia Raffaelli, Leonardo Sorci, Adolfo Amici, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a novel human nicotinamide mononucleotide adenylyltransferase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0006-291x(02)02285-4"}], "href": "https://doi.org/10.1016/s0006-291x(02"}, {"type": "t", "text": "02285-4) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12359228"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12359228"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Leonardo Sorci, Flavio Cimadamore, Stefania Scotti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Initial-rate kinetics of human NMN-adenylyltransferases: substrate and metal ion specificity, inhibition by products and multisubstrate analogues, and isozyme contributions to NAD+ biosynthesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi6023379"}], "href": "https://doi.org/10.1021/bi6023379"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17402747"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17402747"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Paul R Mayer, Nian Huang, Colleen M Dewey, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression, localization, and biochemical characterization of nicotinamide mononucleotide adenylyltransferase 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.178913"}], "href": "https://doi.org/10.1074/jbc.M110.178913"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20943658"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20943658"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Corinna Lau, Christian Dölle, Toni I Gossmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Isoform-specific targeting and interaction domains in human nicotinamide mononucleotide adenylyltransferases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.107631"}], "href": "https://doi.org/10.1074/jbc.M110.107631"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20388704"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20388704"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Joel A Yalowitz, Suhong Xiao, Mangatt P Biju, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of human brain nicotinamide 5'-mononucleotide adenylyltransferase-2 and expression in human pancreas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20030518"}], "href": "https://doi.org/10.1042/BJ20030518"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14516279"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14516279"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Lu-Zhe Pan, Dae-Gyun Ahn, Tanveer Sharif, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The NAD+ synthesizing enzyme nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2) is a p53 downstream target."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Cycle (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/cc.28128"}], "href": "https://doi.org/10.4161/cc.28128"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24552824"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24552824"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Yousuf O Ali, Hunter M Allen, Lei Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Biol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pbio.1002472"}], "href": "https://doi.org/10.1371/journal.pbio.1002472"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27254664"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27254664"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "M Cecilia Ljungberg, Yousuf O Ali, Jie Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddr492"}], "href": "https://doi.org/10.1093/hmg/ddr492"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22027994"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22027994"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Marshall Lukacs, Jonathan Gilley, Yi Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Severe biallelic loss-of-function mutations in nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) in two fetuses with fetal akinesia deformation sequence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Neurol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.expneurol.2019.112961"}], "href": "https://doi.org/10.1016/j.expneurol.2019.112961"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31136762"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31136762"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Peter Huppke, Eike Wegener, Jonathan Gilley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Homozygous NMNAT2 mutation in sisters with polyneuropathy and erythromelalgia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Neurol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.expneurol.2019.112958"}], "href": "https://doi.org/10.1016/j.expneurol.2019.112958"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31132363"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31132363"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Yan Feng, Tingting Yan, Jin Zheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of Wld(S) or Nmnat2 in mauthner cells by single-cell electroporation delays axon degeneration in live zebrafish."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jnr.22498"}], "href": "https://doi.org/10.1002/jnr.22498"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20857515"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20857515"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Muriel Desbois, Oliver Crawley, Paul R Evans, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PAM forms an atypical SCF ubiquitin ligase complex that ubiquitinates and degrades NMNAT2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.RA118.002176"}], "href": "https://doi.org/10.1074/jbc.RA118.002176"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29997255"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29997255"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Xiang-Shu Cheng, Kun-Peng Zhao, Xia Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nmnat2 attenuates Tau phosphorylation through activation of PP2A."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Alzheimers Dis (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3233/JAD-122173"}], "href": "https://doi.org/10.3233/JAD-122173"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23579329"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23579329"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Jae-Jung Kim, Sin Weon Yun, Jeong Jin Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A genome-wide association analysis identifies NMNAT2 and HCP5 as susceptibility loci for Kawasaki disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hum Genet (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/jhg.2017.87"}], "href": "https://doi.org/10.1038/jhg.2017.87"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28855716"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28855716"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Xuan Bi, Liuqing Yang, Tengfei Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide mediation analysis of psychiatric and cognitive traits through imaging phenotypes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Brain Mapp (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/hbm.23650"}], "href": "https://doi.org/10.1002/hbm.23650"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28544218"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28544218"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Kimberly Romero Rosales, Michael A Reid, Ying Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TIPRL Inhibits Protein Phosphatase 4 Activity and Promotes H2AX Phosphorylation in the DNA Damage Response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0145938"}], "href": "https://doi.org/10.1371/journal.pone.0145938"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26717153"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26717153"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Hui Chen, Xiongze Zhang, Nanying Liao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Downregulation of SIRT6 and NMNAT2 is associated with proliferative diabetic retinopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Vis (2023)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38222451"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38222451"}]}]}]}