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Nicotinamide Mononucleotide Adenylyltransferase Expression in Mitochondrial Matrix Delays Wallerian Degeneration
Open accessAbstract
Studies of naturally occurring mutant mice,wld s, showing delayed Wallerian degeneration phenotype, suggest that axonal degeneration is an active process. We previously showed that increased nicotinamide adenine dinucleotide (NAD)-synthesizing activity by overexpression of nicotinamide mononucleotide adenylyltransferase (NMNAT) is the essential component of the Wld s protein, the expression of which is responsible for the delayed Wallerian degeneration phenotype in wld smice. Indeed, NMNAT overexpression in cultured neurons provides robust protection to neurites, as well. To examine the effect of NMNAT overexpression in vivo and to analyze the mechanism that causes axonal protection, we generated transgenic mice (Tg) overexpressing NMNAT1 (nuclear isoform), NMNAT3 (mitochondrial isoform), or the Wld s protein bearing a W258A mutation, which disrupts NAD-synthesizing activity of the Wld s protein. Wallerian degeneration delay in NMNAT3-Tg was similar to that in wld smice, whereas axonal protection in NMNAT1-Tg or Wld s(W258A)-Tg was not detectable. Detailed analysis of subcellular localization of the overexpressed proteins revealed that the axonal protection phenotype was correlated with localization of NMNAT enzymatic activity to mitochondrial matrix. Furthermore, we found that isolated mitochondria from mice showing axonal protection expressed unchanged levels of respiratory chain components, but were capable of increased ATP production. These results suggest that axonal protection by NMNAT expression in neurons is provided by modifying mitochondrial function. Alteration of mitochondrial function may constitute a novel tool for axonal protection, as well as a possible treatment of diseases involving axonopathy.
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“In mammals, over-expressing NMNATs significantly delays Wallerian degeneration of peripheral nerves (28)(29)(30)(31)(32)(33).”
From CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy (2012) · cites this paper as [33]
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“NMNAT3-transgenic mice show delayed Wallerian degeneration similar to Wld S mice (33).”
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Citations
Cites
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Increased Nuclear NAD Biosynthesis and SIRT1 Activation Prevent Axonal Degeneration
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“We showed that exogenously applied NAD results in activation of Sirt1, an NADdependent protein deacetylase, and discussed that this is the key mechanism that connects increased NMNAT activity and axonal protection (Araki et al., 2004).”
BackgroundMethodResultInfluentialSelf-citationPoly(ADP-ribosyl)ation by PARP-1: `PAR-laying' NAD + into a nuclear signalPreprint
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Axonal Self-Destruction and Neurodegeneration
Raff, M., Whitmore, A., & Finn, J. (2002) · Science · doi:10.1126/science.1068613 · Cited by 670 · cited 1×
“Since NMNAT2 is constitutively expressed highly in neurons (Raffaelli et al., 2002), we decided to generate mice that overexpress mammalian NMNAT orthologs other than NMNAT2 (i.e., NMNAT1 and NMNAT3, either of which are unexpressed in neurons) (Emanuelli et al., 2001; Zhang et al., 2003).”
BackgroundAbsence of Wallerian Degeneration does not Hinder Regeneration in Peripheral Nerve
Lunn, E. R., Perry, V. H., Brown, M. C., Rosen, H., & Gordon, S. (1989) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.1989.tb00771.x · Cited by 646
Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene
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“Previous reports suggest that NMNAT3 is located mainly, but not exclusively, in mitochondria when it is transiently overexpressed in cultured cells (Zhang et al., 2003; Berger et al., 2005); however, we found that NMNAT3 was located almost exclusively in mitochondria of NMNAT3-Tg mice.”
BackgroundInfluentialSirtuin Functions in Health and Disease
Yamamoto, H., Schoonjans, K., & Auwerx, J. (2007) · Molecular Endocrinology · doi:10.1210/me.2007-0079 · Cited by 480 · cited 2×
“However, it was not clear how NMNAT overexpression affects Sirt1 activity, because, whereas Sirt1 activity is strictly dependent on intracellular NAD levels (Yamamoto et al., 2007), overexpression of NMNAT activity does not cause major changes in NAD levels (Mack et al.”
BackgroundSuter, M., Riek, U., Tuerk, R. D., Schlattner, U., Wallimann, T., & Neumann, D. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m606357200 · Cited by 473 · cited 2×
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“Mitochondria were isolated from cerebrum as described previously with minor modifications (Sims, 1990; Rajapakse et al., 2001) (also shown in supplemental Fig.”
Method
Cited by
Sorted by citations
Mammalian Sirtuins: Biological Insights and Disease Relevance
Haigis, M. C., & Sinclair, D. A. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev.pathol.4.110807.092250 · Cited by 2,085
Cantó, C., Menzies, K. J., & Auwerx, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.023 · Cited by 1,648
“…activity that is required to delay axon degeneration (Araki et al., 2004; Conforti et al., 2009; Gilley and Coleman, 2010; Llopis et al., 2000; Sasaki et al., 2009; Yahata et al., 2009; Yan et al., 2010), probably by promoting an increase in NAD+-directed SIRT1 activity (Araki et al., 2004).”
BackgroundNAD+ metabolism and its roles in cellular processes during ageing
Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00313-x · Cited by 1,617
Clinical progression in Parkinson disease and the neurobiology of axons
Cheng, H., Ulane, C. M., & Burke, R. E. (2010) · Annals of Neurology · doi:10.1002/ana.21995 · Cited by 1,012
Wallerian degeneration: an emerging axon death pathway linking injury and disease
Conforti, L., Gilley, J., & Coleman, M. P. (2014) · Nature reviews. Neuroscience · doi:10.1038/nrn3680 · Cited by 630
Endogenous Nmnat2 Is an Essential Survival Factor for Maintenance of Healthy Axons
Gilley, J., & Coleman, M. P. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000300 · Cited by 472
“Second, redistribution of predominantly nuclear Wld and Nmnat1 into the cell body and axon enhances their ability to delay Wallerian degeneration [3,7,8].”
BackgroundInfluentialAxon degeneration in Parkinson's disease
Burke, R. E., & O’Malley, K. L. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2012.01.011 · Cited by 514
“Despite WldS being primarily localized in the nucleus, subcellular localization studies have found substantial amounts of WldS within the mitochondrial matrix where it may enhance ATP synthesis (Yahata et al., 2009), prevent free radical formation (Press and Milbrandt, 2008), and/or maintain mitochondrial membrane pot…”
BackgroundInfluentialAxon degeneration: Molecular mechanisms of a self-destruction pathway
Wang, J. T., Medress, Z. A., & Barres, B. A. (2012) · The Journal of Cell Biology · doi:10.1083/jcb.201108111 · Cited by 464
“As the WldS pro tein is also identified in the mitochondria (Yahata et al., 2009), it raises the notion that WldS expression increases Nmnat activ ity at multiple intracellular sites to delay axonal degeneration.”
InfluentialWallerian Degeneration, WldS, and Nmnat
Coleman, M. P., & Freeman, M. R. (2010) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-060909-153248 · Cited by 473
“Another proposal is that Nmnat catalyzes the reverse reaction under stress conditions, which generates an emergency supply of ATP (Yahata et al. 2009), although this appears unlikely to preserve axons for several Annu Rev Neurosci.”
BackgroundResultInfluentialPathways and Subcellular Compartmentation of NAD Biosynthesis in Human Cells
Nikiforov, A., Dölle, C., Niere, M., & Ziegler, M. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.213298 · Cited by 326
Axon Self-Destruction: New Links among SARM1, MAPKs, and NAD+ Metabolism
Gerdts, J., Summers, D. W., Milbrandt, J., & DiAntonio, A. (2016) · Neuron · doi:10.1016/j.neuron.2015.12.023 · Cited by 330
NAD+ Repletion Rescues Female Fertility during Reproductive Aging
Bertoldo, M. J., Listijono, D. R., Ho, W.-H. J., Riepsamen, A. H., Goss, D. M., Richani, D., Jin, X. L., Mahbub, S. B., Campbell, J. M., Habibalahi, A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.01.058 · Cited by 334
“The generation of SIRT2, NMNAT1 and NMNAT3 transgenic mouse strains used here were as previously described (North et al., 2014; Yahata et al., 2009).”
BackgroundMethodInfluentialSelf-citationA rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration
Di Stefano, M., Nascimento-Ferreira, I., Orsomando, G., Mori, V, Gilley, J., Brown, R., Janeckova, L., Vargas, M. E., Worrell, L. A., Loreto, A., et al. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2014.164 · Cited by 246
The Axon-Myelin Unit in Development and Degenerative Disease
Stassart, R. M., Möbius, W., Nave, K.-A., & Edgar, J. M. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00467 · Cited by 246
Mitochondria as a central sensor for axonal degenerative stimuli
Court, F. A., & Coleman, M. P. (2012) · Trends in Neurosciences · doi:10.1016/j.tins.2012.04.001 · Cited by 201
Axonal Degeneration Is Mediated by the Mitochondrial Permeability Transition Pore
Barrientos, S. A., Martínez, N. W., Yoo, S., Jara, J. S., Zamorano, S., Hetz, C. A., Twiss, J. L., Álvarez, J., & Court, F. A. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.4065-10.2011 · Cited by 214
“Mitochondria have been suggested to play an active role in axonal degeneration (Yahata et al., 2009), but the canonical apoptotic pathways have been ruled out (Deckwerth and Johnson, 1994; Sagot et al., 1995; Whitmore et al., Received Aug. 4, 2010; revised Oct. 27, 2010; accepted Nov. 1, 2010.”
BackgroundMechanisms of distal axonal degeneration in peripheral neuropathies
Cashman, C. R., & Höke, A. (2015) · Neuroscience Letters · doi:10.1016/j.neulet.2015.01.048 · Cited by 209
“The secondary activity of Nmnat may be chaperone activity [299] or regulation of mitochondrial metabolism [283].”
Absence of SARM1 Rescues Development and Survival of NMNAT2-Deficient Axons
Gilley, J., Orsomando, G., Nascimento-Ferreira, I., & Coleman, M. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.02.060 · Cited by 196
“Like WLD, each robustly delays Wallerian degeneration when re-localized or sufficiently overexpressed (Mack et al., 2001; Milde et al., 2013; Sasaki et al., 2009; Yahata et al., 2009), but only depletion of NMNAT2, not NMNAT1 or NMNAT3, triggers WLD-sensitive neurite degeneration in neuronal cultures (Gilley and Colem…”
BackgroundThe Highwire Ubiquitin Ligase Promotes Axonal Degeneration by Tuning Levels of Nmnat Protein
Xiong, X., Hao, Y., Sun, K., Li, J., Li, X., Mishra, B., Soppina, P., Wu, C., Hume, R. I., & Collins, C. A. (2012) · PLoS Biology · doi:10.1371/journal.pbio.1001440 · Cited by 202
“The location of its protective action may be the mitochondria, since mitochondrially localized Nmnat can protect axons from degeneration [51,52,59].”
BackgroundSchoenmann, Z., Assa-Kunik, E., Tiomny, S., Minis, A., Haklai-Topper, L., Arama, E., & Yaron, A. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0922-10.2010 · Cited by 147
“Recent studies strongly argue that the enzymatic activity of Nmnat1 within the cytoplasm can account for the neuroprotective effects of Wld S (Avery et al., 2009; Conforti et al., 2009; Sasaki et al., 2009; Yahata et al., 2009).”
BackgroundThe neuroimmunology of degeneration and regeneration in the peripheral nervous system
Oranburg, T. D., Lindborg, J. A., Niemi, J. P., & Zigmond, R. E. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.09.027 · Cited by 180
“To further address this, a variant of the Wlds protein was created that lacked the enzymatic activity of Nmnat1 and resulted in a significant loss of axonal protection (Conforti et al., 2009; Yahata et al., 2009).”
The Phr1 Ubiquitin Ligase Promotes Injury-Induced Axon Self-Destruction
Babetto, E., Beirowski, B., Russler-Germain, E. V., Milbrandt, J., & DiAntonio, A. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.04.013 · Cited by 173
“In mice and humans, there are three isoforms of NMNATs, and each promotes the survival of axonswhen overexpressed (Gilley and Coleman, 2010; Sasaki et al., 2009a; Yahata et al., 2009).”
BackgroundNicotinamide adenine dinucleotide is transported into mammalian mitochondria
Davila, A., Liu, L., Chellappa, K., Redpath, P., Nakamaru-Ogiso, E., Paolella, L. M., Zhang, Z., Migaud, M. E., Rabinowitz, J. D., & Baur, J. A. (2018) · eLife · doi:10.7554/elife.33246 · Cited by 142
Murray, L. M., Talbot, K., & Gillingwater, T. (2010) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2010.01061.x · Cited by 143
Targeting NMNAT1 to Axons and Synapses Transforms Its Neuroprotective PotencyIn Vivo
Babetto, E., Beirowski, B., Janečková, L., Brown, R., Gilley, J., Thomson, D., Ribchester, R. R., & Coleman, M. P. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1189-10.2010 · Cited by 124
“A mitochondrial involvement in the mechanism of WldS and NMNAT1 protection would be in line with recent findings showing that mitochondrial NMNAT3 protects in vivo (Yahata et al., 2009).”
BackgroundResultFang, Y., Soares, L., Teng, X., Geary, M., & Bonini, N. M. (2012) · Current Biology · doi:10.1016/j.cub.2012.01.065 · Cited by 139
“Transgenic mice and flies expressing mNmnat3 achieve axonal protection as potent as Wlds [11,13].”
InfluentialA glycolytic shift in Schwann cells supports injured axons
Babetto, E., Wong, K. M., & Beirowski, B. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0689-4 · Cited by 169
Munemasa, Y., & Kitaoka, Y. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2012.00060 · Cited by 121
Axonal degeneration as a therapeutic target in the CNS
Lingor, P., Koch, J. C., Tönges, L., & Bähr, M. (2012) · Cell and Tissue Research · doi:10.1007/s00441-012-1362-3 · Cited by 119
“This shows not only the potential therapeutic value of NMNAT3 in treating degenerative disease, but also the importance of the subcellular localization of the active substrate.”
BackgroundInfluentialMechanisms of Axonal Spheroid Formation in Central Nervous System Wallerian Degeneration
Beirowski, B., Nógrádi, A., Babetto, E., Garcia-Alias, G., & Coleman, M. P. (2010) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181da84db · Cited by 104
Chandrasekaran, K., Anjaneyulu, M., Choi, J., Kumar, P., Salimian, M., Ho, C.-Y., & Russell, J. W. (2019) · International review of neurobiology · doi:10.1016/bs.irn.2019.04.002 · Cited by 139
Axonal protection by Nmnat3 overexpression with involvement of autophagy in optic nerve degeneration
Kitaoka, Y., Munemasa, Y., Kojima, K., Hirano, A., Ueno, S., & Takagi, H. (2013) · Cell Death & Disease · doi:10.1038/cddis.2013.391 · Cited by 108
“32 Further, it was reported that transgenic mice overexpressing NMNAT3 had a significant number of preserved axons in injured sciatic nerves, whereas wild-type mice had mostly degraded axons in injured nerves.(33) Thus, increased Nmnat3 levels both in vitro and in vivo when using transgenic mice and local overexpressi…”
BackgroundLjungberg, M. C., Ali, Y. O., Zhu, J., Wu, C.-S., Oka, K., Zhai, R. G., & Lu, H.-C. (2012) · Human Molecular Genetics · doi:10.1093/hmg/ddr492 · Cited by 107
“NMNAT3-transgenic mice show delayed Wallerian degeneration similar to Wld mice (33).”
BackgroundVohra, B. P. S., Sasaki, Y., Miller, B. R., Chang, J., DiAntonio, A., & Milbrandt, J. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.2939-10.2010 · Cited by 103
“In support of this hypothesis, overexpression of Wld s, or its component Nmnat, blocks degeneration in response to many distinct stimuli (Mack et al., 2001; Ferri et al., 2003; Araki et al., 2004; Sasaki et al., 2006, 2009a,b; Yahata et al., 2009).”
BackgroundNMNATs, evolutionarily conserved neuronal maintenance factors
Ali, Y. O., Li-Kroeger, D., Bellen, H. J., Zhai, R. G., & Lu, H.-C. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2013.07.002 · Cited by 91
Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma
Inman, D. M., & Harun-Or-Rashid, M. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00146 · Cited by 88
“In vivo, NMNAT1 overexpression was not sufficient for axon protection, but NMNAT3 targeted to the mitochondrial matrix protected sciatic nerves after axotomy (Yahata et al., 2009).”
BackgroundInfluentialWldS and PGC-1α Regulate Mitochondrial Transport and Oxidation State after Axonal Injury
O’Donnell, K. C., Vargas, M. E., & Sagasti, A. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.1331-13.2013 · Cited by 105
“For example, mitochondria isolated from WldS-expressing axons exhibit increased ATP production (Yahata et al., 2009) and calcium buffering (Avery et al., 2012), and a recent study found a correlation between mitochondrial transport and axon protection by WldS (Avery et al., 2012).”
BackgroundMitochondrial Behavior in Axon Degeneration and Regeneration
Wang, B., Huang, M., Shang, D., Yan, X., Zhao, B., & Zhang, X. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.650038 · Cited by 98
“, 2015), the activity of which is greatly inhibited by defects in healthy mitochondria, decreases in mitochondrial transport, and ROS accumulation during axon degeneration (Yahata et al., 2009; Avery et al., 2012; Fang et al., 2012; O’Donnell et al., 2013).”
BackgroundBarrette, B., Calvo, E. L., Vallières, N., & Lacroix, S. (2010) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2010.07.249 · Cited by 96
“…a level of axon protection that is similar (or superior) to that seen in WldS mice (Avery et al., 2009; Beirowski et al., 2009; Sasaki et al., 2009; Yahata et al., 2009), suggests that the function of the N16-VPC/p97 complex may be to relocalize NMNAT1 from the nuclear to the cyto- solic and…”
Nmnat2 delays axon degeneration in superior cervical ganglia dependent on its NAD synthesis activity
Yan, T., Feng, Y., Zheng, J., Ge, X., Zhang, Y., Wu, D., Zhao, J., & Zhai, Q. (2010) · Neurochemistry International · doi:10.1016/j.neuint.2009.09.007 · Cited by 92
Axonal Degeneration in AD: The Contribution of Aβ and Tau
Salvadores, N., Gerónimo‐Olvera, C., & Court, F. A. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.581767 · Cited by 101
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“In PNS-derived neurons injured by axotomy, NR is protective reportedly because Nmrk2 is transcriptionally up-regulated by the injury (7).”
BackgroundInfluentialKilinc, D., Peyrin, J., Soubeyre, V., Magnifico, S., Saïas, L., Viovy, J., & Brugg, B. (2010) · Neurotoxicity Research · doi:10.1007/s12640-010-9152-8 · Cited by 88
“2004) but not in vivo axotomy (Conforti et al. 2007; Yahata et al. 2009).”
Autophagy in axonal degeneration in glaucomatous optic neuropathy
Munemasa, Y., & Kitaoka, Y. (2015) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2015.03.002 · Cited by 82
Hikosaka, K., Ikutani, M., Shito, M., Kazuma, K., Gulshan, M., Nagai, Y., Takatsu, K., Konno, K., Tobe, K., Kanno, H., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.554378 · Cited by 81
“Nmnat3 overexpression confers robust protection against axon injury in vitro and in vivo as well as WldS chimeric protein (27, 28).”
BackgroundA Model of Toxic Neuropathy inDrosophilaReveals a Role for MORN4 in Promoting Axonal Degeneration
Bhattacharya, M. R. C., Gerdts, J., Naylor, S. A., Royse, E. X., Ebstein, S. Y., Sasaki, Y., Milbrandt, J., & DiAntonio, A. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.4951-11.2012 · Cited by 75
“…includes the mitochondrial permeability transition pore (Forte et al., 2007; Barrientos et al., 2011) and can be blocked by axonal expression of NMNAT isoforms (Araki et al., 2004; Conforti et al., 2009; Sasaki et al., 2009a; Yahata et al., 2009; Babetto et al., 2010; Sasaki and Milbrandt, 2010).”
BackgroundSignaling mechanisms regulating Wallerian degeneration
Freeman, M. R. (2014) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.05.001 · Cited by 78
Kitay, B. M., McCormack, R., Wang, Y., Tsoulfas, P., & Zhai, R. G. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt009 · Cited by 77
Chandrasekaran, K., Salimian, M., Konduru, S. R., Choi, J., Kumar, P., Long, A., Klimova, N., Ho, C.-Y., Kristián, T., & Russell, J. W. (2019) · Brain · doi:10.1093/brain/awz324 · Cited by 72
“Proteins that resynthesize NAD + via the salvage pathway such as NMNAT1–3, protect against axonal degeneration (Araki et al., 2004; Press and Milbrandt, 2008; Sasaki et al., 2009; Yahata et al., 2009; Babetto et al., 2010; Gilley and Coleman, 2010; Di Stefano et al., 2017).”
BackgroundZhu, Y., Zhang, L., Sasaki, Y., Milbrandt, J., & Gidday, J. M. (2012) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.12-10861 · Cited by 66
Tao, J., & Rolls, M. M. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.3826-10.2011 · Cited by 66
The Synaptic Proteome during Development and Plasticity of the Mouse Visual Cortex
Dahlhaus, M., Li, K. W., van der Schors, R. C., Saiepour, M. H., van Nierop, P., Heimel, J. A., Hermans, J. M., Loos, M., Smit, A. B., & Levelt, C. N. (2011) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m110.005413 · Cited by 60
“Several mechanisms have been implicated and include reduced mitochondrial activity (53), alterations in the ubiquitin/proteasome system (54), increased microtubule The Synaptic Proteome during Visual Plasticity”
BackgroundNMNAT: It’s an NAD+ synthase… It’s a chaperone… It’s a neuroprotector
Brazill, J. M., Li, C. V., Zhu, Y., & Zhai, R. G. (2017) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2017.03.014 · Cited by 74
Felici, R., Lapucci, A., Ramazzotti, M., & Chiarugi, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076938 · Cited by 63
“Later on, almost all the information collected on NMNAT3 localization and activity has been obtained by expression plasmids coding for tagged proteins [9,12,14].”
BackgroundNmnat exerts neuroprotective effects in dendrites and axons
Wen, Y., Parrish, J. Z., He, R., Zhai, R. G., & Kim, M. D. (2011) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2011.05.002 · Cited by 49
“…that the enzymatic activity of Nmnat is required for axonal protection (Avery et al., 2009; Conforti et al., 2009; Jia et al., 2007; Sasaki et al., 2009; Yahata et al., 2009; Yan et al., 2010), these studies have not directly addressed a neuroprotective role for Nmnat specifically in dendrites.”
BackgroundImplications of NAD metabolism in pathophysiology and therapeutics for neurodegenerative diseases
Hikosaka, K., Yaku, K., Okabe, K., & Nakagawa, T. (2021) · Nutritional Neuroscience · doi:10.1080/1028415x.2019.1637504 · Cited by 62
Sasaki, Y., & Milbrandt, J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.c110.193904 · Cited by 66
Peters, O. M., Lewis, E. A., Osterloh, J. M., Weiss, A., Salameh, J. S., Metterville, J., Brown, R. H., & Freeman, M. R. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy260 · Cited by 64
“Both proteins localize to mitochondria (33–35), with Sarm1 robustly protecting cultured neurons from the downstream reactive oxygen stress caused by mitochondria uncoupling (36).”
BackgroundAxon Degeneration and Regeneration: Insights from Drosophila Models of Nerve Injury
Fang, Y., & Bonini, N. M. (2012) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-101011-155836 · Cited by 59
Arthur‐Farraj, P., & Coleman, M. P. (2021) · Neurotherapeutics · doi:10.1007/s13311-021-01125-3 · Cited by 63
Ocampo, A., Liu, J., & Barrientos, A. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt016 · Cited by 47
NAD+: A key metabolic regulator with great therapeutic potential
Sultani, G., Samsudeen, A., Osborne, B., & Turner, N. A. (2017) · Journal of Neuroendocrinology · doi:10.1111/jne.12508 · Cited by 54
Owens, K., Park, J. H., Schuh, R. A., & Kristián, T. (2013) · Translational Stroke Research · doi:10.1007/s12975-013-0278-x · Cited by 51
Kuo, C.-C., Su, H., Chang, T.-L., Chiang, C.-Y., Sheu, M., Cheng, F., Chen, C., Sheehan, J. P., & Pan, H.-C. (2017) · Neurosurgery · doi:10.1093/neuros/nyw090 · Cited by 54
Concepts for regulation of axon integrity by enwrapping glia
Beirowski, B. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00256 · Cited by 47
“This cytoplasmic NAD+ dependent sirtuin has been recently implicated in cellautonomous axonal stability mechanisms, toxin-induced axon degeneration, and the pathways mediating the WldS phenotype (Suzuki and Koike, 2007a,b; Wishart et al., 2012).”
BackgroundInfluentialThe role of autophagy in axonal degeneration of the optic nerve
Koch, J. C., & Lingor, P. (2016) · Experimental Eye Research · doi:10.1016/j.exer.2015.08.016 · Cited by 46
NAD + acts on mitochondrial SirT3 to prevent axonal caspase activation and axonal degeneration
Magnifico, S., Saïas, L., Deleglise, B., Duplus, E., Kilinc, D., Miquel, M., Viovy, J., Brugg, B., & Peyrin, J. (2013) · The FASEB Journal · doi:10.1096/fj.13-229781 · Cited by 54
“Accordingly, a recent study showed that overexpression of NMNAT3, a NAD producing enzyme, in the mitochondrial matrix increased axonal resistance to axotomy, suggesting that NMNAT-dependent axonal protection involves modulation of mitochondrial function modulation (55).”
BackgroundMilde, S., Fox, A. N., Freeman, M. R., & Coleman, M. P. (2013) · Scientific Reports · doi:10.1038/srep02567 · Cited by 45
Gulshan, M., Yaku, K., Okabe, K., Mahmood, A., Sasaki, T., Yamamoto, M., Hikosaka, K., Usui, I., Kitamura, T., Tobe, K., et al. (2018) · Aging Cell · doi:10.1111/acel.12798 · Cited by 49
“Nmnat3 mice were generated as described previously (Yahata et al., 2009).”
MethodFeng, Y., Yan, T., Zheng, J. H., Ge, X., Mu, Y., Zhang, Y., Wu, D., Du, J., & Zhai, Q. (2010) · Journal of Neuroscience Research · doi:10.1002/jnr.22498 · Cited by 46
“Overexpression of Nmnat3 protects axons in mice and Drosophila as well (Avery et al., 2009; Yahata et al., 2009).”
BackgroundLocal axonal protection by WldS as revealed by conditional regulation of protein stability
Wang, J. T., Medress, Z. A., Vargas, M. E., & Barres, B. A. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1508337112 · Cited by 48
“Although the WldS protein is localized predominantly in the nucleus because of the endogenous nuclear localization of Nmnat1, trace amounts of WldS protein also have been identified in extranuclear compartments in the axoplasm and in axonal organelles including the mitochondria and phagosomes (10, 11), suggesting that…”
BackgroundThe Role of Axonopathy in Parkinson's Disease
O’Malley, K. L. (2010) · Experimental Neurobiology · doi:10.5607/en.2010.19.3.115 · Cited by 33
“…subcellular localization studies have found substantial amounts of Wld S within the mitochondrial matrix where it may en-118 hance ATP synthesis (Yahata et al., 2009), prevent free radical formation (Press and Milbrandt, 2009), or maintain mitochondrial membrane potential (Ike-gami and Koike,…”
A Novel NAD Signaling Mechanism in Axon Degeneration and its Relationship to Innate Immunity
Hopkins, E. L., Gu, W., Kobe, B., & Coleman, M. P. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.703532 · Cited by 48
Preserve and protect: maintaining axons within functional circuits
Pease-Raissi, S. E., & Segal, R. A. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2014.07.007 · Cited by 36
Mechanisms and repair strategies for white matter degeneration in CNS injury and diseases
Shahsavani, N., Kataria, H., & Karimi‐Abdolrezaee, S. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2021.166117 · Cited by 43
Yaku, K., Okabe, K., Gulshan, M., Takatsu, K., Okamoto, H., & Nakagawa, T. (2019) · Scientific Reports · doi:10.1038/s41598-019-49547-6 · Cited by 38
Ali, Y., Bradley, G., & Lu, H. (2017) · Scientific Reports · doi:10.1038/srep43846 · Cited by 43
Vitamin B3, the nicotinamide adenine dinucleotides and aging
Xu, P., & Sauve, A. A. (2010) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2010.03.006 · Cited by 38
“Strikingly, NADand NAD precursors can also provide protection against axonal degeneration, suggesting that the effect of Nmnat1 is achieved through a function involving NAD synthesis (Sasaki et al., 2006, 2009; Press and Milbrandt, 2008; Wang and He, 2009; Yahata et al., 2009).”
BackgroundAxon degeneration: Mechanisms and implications of a distinct program from cell death
Yan, T., Feng, Y., & Zhai, Q. (2010) · Neurochemistry International · doi:10.1016/j.neuint.2010.01.013 · Cited by 36
“Studies suggested that overexpression of Wld and Nmnat1 might initiate their axonal protective function by increasing mitochondrial NAD or ATP production (Sasaki et al., 2009b; Yahata et al., 2009).”
InfluentialChandrasekaran, K., Najimi, N., Sagi, A. R., Yarlagadda, S., Salimian, M., Arvas, M. I., Hedayat, A. F., Kevas, Y., Kadakia, A., & Russell, J. W. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094887 · Cited by 37
Simultaneous Single-Sample Determination of NMNAT Isozyme Activities in Mouse Tissues
Orsomando, G., Cialabrini, L., Amici, A., Mazzola, F., Ruggieri, S., Conforti, L., Janečková, L., Coleman, M. P., & Magni, G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0053271 · Cited by 35
“subcellular district [43,44], 3) incomplete recovery of a given”
BackgroundWldS but not Nmnat1 protects dopaminergic neurites from MPP+ neurotoxicity
Antenor‐Dorsey, J. A. V., & O’Malley, K. L. (2012) · Molecular Neurodegeneration · doi:10.1186/1750-1326-7-5 · Cited by 29
“In contrast, transgenic animals expressing nuclear Nmnat1 did not replicate the effects of Wld [42,43] whereas cytoplasmically [39] or axonally targeted Nmnat1 [34] were equally if not more effective.”
Hayes, L. R., Brotherton, T. E., & Glass, J. D. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2013.05.001 · Cited by 37
Poly(ADP-ribose) polymerase 1 is a novel target to promote axonal regeneration
Brochier, C., Jones, J. I., Willis, D. E., & Langley, B. C. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1509754112 · Cited by 39
“Underscoring the importance of axonal NAD+, many studies have shown that increasing axonal NAD+ via extra copies of the NAD+ recycling enzyme NMNAT (22, 54, 55) or providing exogenous NAD+ or its precursors can markedly delay axon degeneration after transection (22).”
BackgroundMaintaining energy homeostasis is an essential component of WldS-mediated axon protection
Shen, H., Hyrc, K. L., & Goldberg, M. P. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.07.007 · Cited by 36
“There is compelling evidence indicating that NMNAT activity is required for WldS-mediated axon protection (Araki et al., 2004; Avery et al., 2009; Conforti et al., 2009; Yahata et al., 2009).”
BackgroundWilliams, A. C., Hill, L. J., & Ramsden, D. B. (2012) · Current Gerontology and Geriatrics Research · doi:10.1155/2012/302875 · Cited by 42
“Recent reviews on nicotinamide and NAD metabolism, evolution and function concentrate on its pivotal role in gene silencing, development and ageing, through recently appreciated NAD consumers, such as the sirtuins (SIRTs) [77–85], that evolved to work in large part as nutrientsensing regulators, and poly (ADP ribose)…”
BackgroundNicotinamide and neurocognitive function
Rennie, G. E., Chen, A. C., Dhillon, H. M., Vardy, J. L., & Damian, D. L. (2014) · Nutritional Neuroscience · doi:10.1179/1476830514y.0000000112 · Cited by 40
Axonal fusion: An alternative and efficient mechanism of nerve repair
Neumann, B., Linton, C., Giordano-Santini, R., & Hilliard, M. A. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.11.004 · Cited by 34
Coppedè, F., Bosco, P., Fuso, A., & Troen, A. M. (2012) · Current Gerontology and Geriatrics Research · doi:10.1155/2012/926082 · Cited by 5
The Molecular Interplay between Axon Degeneration and Regeneration
Girouard, M., Bueno, M., Julian, V., Drake, S., Byrne, A. B., & Fournier, A. E. (2018) · Developmental Neurobiology · doi:10.1002/dneu.22627 · Cited by 42
“Its activity partly depends on mitochondria and correlates with mitochondrial preservation, enhanced mitochondrial motility, and reactive oxygen species (ROS) stabilization (Yahata et al., 2009; Avery et al., 2012; Fang et al., 2012; O’Donnell et al., 2013).”
BackgroundWldS, Nmnats and axon degeneration-progress in the past two decades
Feng, Y., Yan, T., He, Z., & Zhai, Q. (2010) · Protein & Cell · doi:10.1007/s13238-010-0021-2 · Cited by 24
“Interestingly, Nmnat3 transgenic mice showed robust protection as Wld (Yahata et al., 2009), again supporting the protective effects of non-nuclear Nmnat and Wld proteins.”
BackgroundMethodInfluentialGlutamate signals through mGluR2 to control Schwann cell differentiation and proliferation
Saitoh, F., Wakatsuki, S., Tokunaga, S., Fujieda, H., & Araki, T. (2016) · Scientific Reports · doi:10.1038/srep29856 · Cited by 28
Self-citationMcGuinness, H. Y., Gu, W., Shi, Y. Y., Kobe, B., & Ve, T. (2023) · The Neuroscientist · doi:10.1177/10738584231162508 · Cited by 29
Axonal transport plays a crucial role in mediating the axon-protective effects of NmNAT
Fang, C., Decker, H., & Banker, G. A. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.04.013 · Cited by 19
“Moreover, mitochondria from Wld mice have an enhanced ability to generate ATP (Yahata et al., 2009) and expression of the Wld protein or various forms of NmNAT in cultured neurons reduces the decline in ATP levels that occur following axotomy (Wang et al.”
InfluentialMolecular chaperones protect against JNK- and Nmnat-regulated axon degeneration in Drosophila
Rallis, A., Lu, B., & Ng, J. (2012) · Journal of Cell Science · doi:10.1242/jcs.117259 · Cited by 19
Molecular mechanisms in the initiation phase of Wallerian degeneration
Chang, B., Quan, Q., Lu, S., Wang, Y., & Peng, J. (2016) · European Journal of Neuroscience · doi:10.1111/ejn.13250 · Cited by 22
“Although WLDs is predominantly located in nuclei, small quantities of WLDs are present in the axonal pool (Mack et al., 2001; Beirowski et al., 2005; Yahata et al., 2009).”
BackgroundAxon Degeneration: Where the Wlds Things Are
Wang, J. T., & Barres, B. A. (2012) · Current Biology · doi:10.1016/j.cub.2012.02.056 · Cited by 18
Pathobiochemistry of Aging and Neurodegeneration: Deregulation of NAD+ Metabolism in Brain Cells
Kolotyeva, N. A., Groshkov, A. A., Rozanova, N. A., Berdnikov, A. K., Novikova, S. V., Komleva, Y. K., Salmina, A. B., Illarioshkin, S. N., & Пирадов, М. А. (2024) · Biomolecules · doi:10.3390/biom14121556 · Cited by 24
“It was proposed that the subcellular distribution of NMNATs may dictate their organelle-specific functions [54–57].”
Moss, K. R., & Höke, A. (2019) · Brain Research · doi:10.1016/j.brainres.2019.146539 · Cited by 25
Intracellular signalling pathways in dopamine cell death and axonal degeneration
Burke, R. E. (2010) · Progress in brain research · doi:10.1016/s0079-6123(10)83005-5 · Cited by 22
“Interestingly, the full protection phenotype can be observed in experiments with NMNAT3, a mitochondrially targeted isoform (Avery et al., 2009; Sasaki et al., 2006; Yahata et al., 2009).”
Background
Metadata
- Authors
- Yahata, N., Yuasa, S., & Araki, T.
- Affiliations
- National Center of Neurology and Psychiatry (JP)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-05-13
- Volume
- 29
- Issue
- 19
- Pages
- 6276-6284
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6665489
- OpenAlex
- W2037726118
- Cited by
- 154
- References
- 30
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 6 · 2021: 10 · 2020: 5 · 2019: 8 · 2018: 10 · 2017: 8 · 2016: 5 · 2015: 10 · 2014: 12 · 2013: 16 · 2012: 16
- FWCI
- 7.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Suzuken Memorial Foundation
- Kowa Company
- Kowa Life Science Foundation
- Astellas Pharma
- National Institute of Biomedical Innovation
- Astellas Foundation for Research on Metabolic Disorders
- Mishima Kaiun Memorial Foundation
- Japan Society for the Promotion of Science (19650089)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- nicotinamide mononucleotide adenylyltransferase, NMNAT3, NMNAT1, Wallerian degeneration, axonal degeneration, axonal protection, mitochondrial matrix, NAD biosynthesis, mitochondrial function, ATP production, transgenic mice, axonopathy
- MeSH terms
- Adenosine Triphosphate, Animals, Axons, Electron Transport, Mice, Transgenic, Mitochondria, Nerve Tissue Proteins, Neurons, Nicotinamide-Nucleotide Adenylyltransferase, Sciatic Nerve, Wallerian Degeneration, Mutation, Missense, Sciatic Neuropathy, Mice
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