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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
Efficient selection for high-expression transfectants with a novel eukaryotic vector
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Increased Nuclear NAD Biosynthesis and SIRT1 Activation Prevent Axonal Degeneration
Araki, T., Sasaki, Y., & Milbrandt, J. (2004) · Science · doi:10.1126/science.1098014 · Cited by 1,060 · cited 12×
“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
Kim, M. Y., Zhang, T., & Kraus, W. L. (2005) · Genes & Development · doi:10.1101/gad.1331805 · Cited by 826
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
Mack, T. G. A., Reiner, M., Beirowski, B., Mi, W., Emanuelli, M., Wagner, D., Thomson, D., Gillingwater, T., Court, F., Conforti, L., et al. (2001) · Nature Neuroscience · doi:10.1038/nn770 · Cited by 611
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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×
“anion-exchange column as described previously (Suter et al., 2006).”
MethodSims, N. (1990) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1990.tb04189.x · Cited by 388 · cited 1×
“Mitochondria were isolated from cerebrum as described previously with minor modifications (Sims, 1990; Rajapakse et al., 2001) (also shown in supplemental Fig.”
MethodRapid accumulation of Akt in mitochondria following phosphatidylinositol 3‐kinase activation
Bijur, G. N., & Jope, R. S. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.02113.x · Cited by 330 · cited 2×
“Purified synaptic mitochondria were subfractionated by using a phosphate swelling–shrinking method described previously (Bijur and Jope, 2003), with minor modifications to obtain fractions containing outer membrane, intermembrane space, inner membrane, and matrix.”
MethodSasaki, Y., Araki, T., & Milbrandt, J. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.2320-06.2006 · Cited by 269 · cited 5×
“We showed in a previous report that lentiviral NMNAT1 overexpression in primary cultured neurons results in the axonal protection phenotype in the Wallerian degeneration model in vitro (Araki et al., 2004; Sasaki et al., 2006).”
BackgroundMethodInfluentialSelf-citationConforti, L., Tarlton, A., Mack, T. G. A., Mi, W., Buckmaster, E. A., Wagner, D., Perry, V. H., & Coleman, M. P. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.21.11377 · Cited by 251
NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration
Zhai, R. G., Zhang, F., Hiesinger, P. R., Cao, Y., Haueter, C. M., & Bellen, H. J. (2008) · Nature · doi:10.1038/nature06721 · Cited by 201 · cited 1×
“This chaperonelike activity is independent from NAD-synthesizing activity of NMNAT (Zhai et al., 2008).”
BackgroundEmanuelli, M., Carnevali, F., Saccucci, F., Pierella, F., Amici, A., Raffaelli, N., & Magni, G. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008700200 · Cited by 189
Tateno, M., Sadakata, H., Tanaka, M., Itohara, S., Shin, R.-M., Miura, M., Masuda, M., Aosaki, T., Urushitani, M., Misawa, H., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh246 · Cited by 150 · cited 1×
“Fractionation of adult mouse cerebrum to obtain nucleus, mitochondria, lysosome/peroxysome, microsome, and cytosol fractions was performed by sequential centrifugation as described previously (Tateno et al., 2004) (also shown in Fig.”
MethodConforti, L., Fang, G., Beirowski, B., Wang, M. S., Sorci, L., Asress, S., Adalbert, R., Silva, A., Bridge, K., Huang, X. P., et al. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401944 · Cited by 137 · cited 3×
“However, Coleman et al. showed that NMNAT1-overexpressing mice did not show an axonal protection phenotype and speculated that axonal protection by NMNAT overexpression may only be observed in in vitro settings (Conforti et al., 2007).”
BackgroundNmnat delays axonal degeneration caused by mitochondrial and oxidative stress
Press, C., & Milbrandt, J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.0525-08.2008 · Cited by 137
Zhang, X., Kurnasov, O. V., Karthikeyan, S., Grishin, N. V., Osterman, A. L., & Zhang, H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300073200 · Cited by 136 · cited 4×
“, NMNAT1 and NMNAT3, either of which are unexpressed in neurons) (Emanuelli et al., 2001; Zhang et al., 2003).”
BackgroundInfluentialIdentification of a novel human nicotinamide mononucleotide adenylyltransferase
Raffaelli, N., Sorci, L., Amici, A., Emanuelli, M., Mazzola, F., & Magni, G. (2002) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)02285-4 · Cited by 127 · 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).”
BackgroundMitochondrial Proteomic Analysis of a Cell Line Model of Familial Amyotrophic Lateral Sclerosis
Fukada, K., Zhang, F., Vien, A., Cashman, N. R., & Zhu, H. (2004) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m400094-mcp200 · Cited by 121
Baracca, A., Barogi, S., Carelli, V., Lenaz, G., & Solaini, G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.6.4177 · Cited by 112 · cited 1×
“The citrate-sustained ATP-synthetic rate was assayed by a modified procedure as described previously (Baracca et al., 2000; Shaik et al., 2008).”
MethodIkegami, K., & Koike, T. (2003) · Neuroscience · doi:10.1016/j.neuroscience.2003.08.057 · Cited by 105
Wishart, T. M., Paterson, J. M., Short, D. M., Meredith, S., Robertson, K. A., Sutherland, C. D., Cousin, M. A., Dutia, M. B., & Gillingwater, T. H. (2007) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m600457-mcp200 · Cited by 86 · cited 2×
“Previous reports on axonal protection observed in wlds mice suggested possible significance of mitochondrial function (Ikegami and Koike, 2003; Wishart et al., 2007; Press and Milbrandt, 2008).”
BackgroundAssay methods for nicotinamide mononucleotide adenylyltransferase of wide applicability.
Balducci, E., Emanuelli, M., Raffaelli, N., Ruggieri, S., Amici, A., Magni, G., Orsomando, G., Polzonetti, V., & Natalini, P. (1995) · Analytical Biochemistry · doi:10.1006/abio.1995.1315 · Cited by 79 · cited 1×
“NMNAT activity was measured by SpectraMax M2 (Molecular Devices) at 37°C on 96-well plates, based on the procedure as previously described (Balducci et al., 1995).”
MethodIsolation and characterization of intact mitochondria from neonatal rat brain.
Rajapakse, N. C., Shimizu, K., Payne, M., & Busija, D. (2001) · Brain research. Brain research protocols · doi:10.1016/s1385-299x(01)00108-8 · Cited by 74 · cited 1×
“Mitochondria were isolated from cerebrum as described previously with minor modifications (Sims, 1990; Rajapakse et al., 2001) (also shown in supplemental Fig.”
MethodLaser, H., Conforti, L., Morreale, G., Mack, T. G. A., Heyer, M., Haley, J. E., Wishart, T. M., Beirowski, B., Walker, S. A., Haase, G., et al. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-04-0375 · Cited by 61
Shaik, Z. P., Fifer, E., & Nowak, G. (2008) · AJP - Renal Physiology · doi:10.1152/ajprenal.00463.2007 · Cited by 49 · cited 1×
“The citrate-sustained ATP-synthetic rate was assayed by a modified procedure as described previously (Baracca et al., 2000; Shaik et al., 2008).”
MethodTransgenic Mouse Production By Zygote Injection
Conner, D. (2004) · Current Protocols in Molecular Biology · doi:10.1002/0471142727.mb2309s68 · Cited by 15 · cited 1×
“Transgenic constructs were microinjected into fertilized BDF1 mouse oocytes by following standard procedure (Conner, 2004).”
Method
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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
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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