Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2024

Open Access 01-12-2024 | Research article

NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport

Authors: Sen Yang, Zhen-Xian Niou, Andrea Enriquez, Jacob LaMar, Jui-Yen Huang, Karen Ling, Paymaan Jafar-Nejad, Jonathan Gilley, Michael P. Coleman, Jason M. Tennessen, Vidhya Rangaraju, Hui-Chen Lu

Published in: Molecular Neurodegeneration | Issue 1/2024

Login to get access

Abstract

Background

Bioenergetic maladaptations and axonopathy are often found in the early stages of neurodegeneration. Nicotinamide adenine dinucleotide (NAD), an essential cofactor for energy metabolism, is mainly synthesized by Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) in CNS neurons. NMNAT2 mRNA levels are reduced in the brains of Alzheimer’s, Parkinson’s, and Huntington’s disease. Here we addressed whether NMNAT2 is required for axonal health of cortical glutamatergic neurons, whose long-projecting axons are often vulnerable in neurodegenerative conditions. We also tested if NMNAT2 maintains axonal health by ensuring axonal ATP levels for axonal transport, critical for axonal function.

Methods

We generated mouse and cultured neuron models to determine the impact of NMNAT2 loss from cortical glutamatergic neurons on axonal transport, energetic metabolism, and morphological integrity. In addition, we determined if exogenous NAD supplementation or inhibiting a NAD hydrolase, sterile alpha and TIR motif-containing protein 1 (SARM1), prevented axonal deficits caused by NMNAT2 loss. This study used a combination of techniques, including genetics, molecular biology, immunohistochemistry, biochemistry, fluorescent time-lapse imaging, live imaging with optical sensors, and anti-sense oligos.

Results

We provide in vivo evidence that NMNAT2 in glutamatergic neurons is required for axonal survival. Using in vivo and in vitro studies, we demonstrate that NMNAT2 maintains the NAD-redox potential to provide “on-board” ATP via glycolysis to vesicular cargos in distal axons. Exogenous NAD+ supplementation to NMNAT2 KO neurons restores glycolysis and resumes fast axonal transport. Finally, we demonstrate both in vitro and in vivo that reducing the activity of SARM1, an NAD degradation enzyme, can reduce axonal transport deficits and suppress axon degeneration in NMNAT2 KO neurons.

Conclusion

NMNAT2 ensures axonal health by maintaining NAD redox potential in distal axons to ensure efficient vesicular glycolysis required for fast axonal transport.
Appendix
Available only for authorised users
Literature
1.
2.
3.
Shokhirev MN, Johnson AA. An integrative machine-learning meta-analysis of high-throughput omics data identifies age-specific hallmarks of Alzheimer’s disease. Ageing Res Rev. 2022;81:101721.PubMedCrossRef
4.
Roy M, Rheault F, Croteau E, Castellano CA, Fortier M, St-Pierre V, Houde JC, Turcotte EE, Bocti C, Fulop T, et al. Fascicle- and Glucose-Specific Deterioration in White Matter Energy Supply in Alzheimer’s Disease. J Alzheimers Dis. 2020;76:863–81.PubMedCrossRef
5.
Wang M, Liu K, Pan J, Li J, Sun P, Zhang Y, Li L, Guo W, Xin Q, Zhao Z, et al. Brain-wide projection reconstruction of single functionally defined neurons. Nat Commun. 2022;13:1531.PubMedPubMedCentralCrossRef
6.
Winnubst J, Bas E, Ferreira TA, Wu Z, Economo MN, Edson P, Arthur BJ, Bruns C, Rokicki K, Schauder D, et al. Reconstruction of 1,000 Projection Neurons Reveals New Cell Types and Organization of Long-Range Connectivity in the Mouse Brain. Cell. 2019;179(268–281):e213.
7.
Peng H, Xie P, Liu L, Kuang X, Wang Y, Qu L, Gong H, Jiang S, Li A, Ruan Z, et al. Morphological diversity of single neurons in molecularly defined cell types. Nature. 2021;598:174–81.PubMedPubMedCentralCrossRef
8.
Coleman MP. The challenges of axon survival: introduction to the special issue on axonal degeneration. Exp Neurol. 2013;246:1–5.PubMedCrossRef
9.
Zhang J, Long B, Li A, Sun Q, Tian J, Luo T, Ding Z, Gong H, Li X. Whole-Brain Three-Dimensional Profiling Reveals Brain Region Specific Axon Vulnerability in 5xFAD Mouse Model. Front Neuroanat. 2020;14:608177.PubMedPubMedCentralCrossRef
10.
Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS. Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science. 2005;307:1282–8.PubMedCrossRef
11.
Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, Khan J, Polak MA, Glass JD. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol. 2004;185:232–40.PubMedCrossRef
12.
Xiao AW, He J, Wang Q, Luo Y, Sun Y, Zhou YP, Guan Y, Lucassen PJ, Dai JP. The origin and development of plaques and phosphorylated tau are associated with axonopathy in Alzheimer’s disease. Neurosci Bull. 2011;27:287–99.PubMedPubMedCentralCrossRef
13.
14.
Berger F, Lau C, Dahlmann M, Ziegler M. Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms. J Biol Chem. 2005;280:36334–41.PubMedCrossRef
15.
Raffaelli N, Sorci L, Amici A, Emanuelli M, Mazzola F, Magni G. Identification of a novel human nicotinamide mononucleotide adenylyltransferase. Biochem Biophys Res Commun. 2002;297:835–40.PubMedCrossRef
16.
Yan T, Feng Y, Zheng J, Ge X, Zhang Y, Wu D, Zhao J, Zhai Q. Nmnat2 delays axon degeneration in superior cervical ganglia dependent on its NAD synthesis activity. Neurochem Int. 2010;56:101–6.PubMedCrossRef
17.
18.
19.
Simon DJ, Watkins TA. Therapeutic opportunities and pitfalls in the treatment of axon degeneration. Curr Opin Neurol. 2018;31:693–701.PubMedCrossRef
20.
21.
Ali YO, Allen HM, Yu L, Li-Kroeger D, Bakhshizadehmahmoudi D, Hatcher A, McCabe C, Xu J, Bjorklund N, Taglialatela G, et al. NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies. PLoS Biol. 2016;14:e1002472.PubMedPubMedCentralCrossRef
22.
Bennett JP, Keeney PM. RNA-Sequencing Reveals Similarities and Differences in Gene Expression in Vulnerable Brain Tissues of Alzheimer’s and Parkinson’s Diseases. J Alzheimers Dis Rep. 2018;2:129–37.PubMedPubMedCentralCrossRef
23.
Ali YO, Li-Kroeger D, Bellen HJ, Zhai RG, Lu HC. NMNATs, evolutionarily conserved neuronal maintenance factors. Trends Neurosci. 2013;36:632–40.PubMedCrossRef
24.
Brazill JM, Li C, Zhu Y, Zhai RG. NMNAT: It’s an NAD(+) synthase... It’s a chaperone... It’s a neuroprotector. Curr Opin Genet Dev. 2017;44:156–62.PubMedPubMedCentralCrossRef
25.
Milde S, Gilley J, Coleman MP. Subcellular localization determines the stability and axon protective capacity of axon survival factor Nmnat2. PLoS Biol. 2013;11:e1001539.PubMedPubMedCentralCrossRef
26.
Hung CO, Coleman MP. KIF1A mediates axonal transport of BACE1 and identification of independently moving cargoes in living SCG neurons. Traffic. 2016;17:1155–67.PubMedPubMedCentralCrossRef
27.
Guedes-Dias P, Holzbaur ELF: Axonal transport: Driving synaptic function. Science 2019, 366.
28.
Sleigh JN, Rossor AM, Fellows AD, Tosolini AP, Schiavo G. Axonal transport and neurological disease. Nat Rev Neurol. 2019;15:691–703.PubMedCrossRef
29.
Pacelli C, Giguere N, Bourque MJ, Levesque M, Slack RS, Trudeau LE. Elevated Mitochondrial Bioenergetics and Axonal Arborization Size Are Key Contributors to the Vulnerability of Dopamine Neurons. Curr Biol. 2015;25:2349–60.PubMedCrossRef
30.
31.
32.
Zala D, Hinckelmann MV, Yu H. Lyra da Cunha MM, Liot G, Cordelieres FP, Marco S, Saudou F: Vesicular glycolysis provides on-board energy for fast axonal transport. Cell. 2013;152:479–91.PubMedCrossRef
33.
34.
Faitg J, Lacefield C, Davey T, White K, Laws R, Kosmidis S, Reeve AK, Kandel ER, Vincent AE, Picard M. 3D neuronal mitochondrial morphology in axons, dendrites, and somata of the aging mouse hippocampus. Cell Rep. 2021;36:109509.PubMedPubMedCentralCrossRef
35.
Santuy A, Turegano-Lopez M, Rodriguez JR, Alonso-Nanclares L, DeFelipe J, Merchan-Perez A. A Quantitative Study on the Distribution of Mitochondria in the Neuropil of the Juvenile Rat Somatosensory Cortex. Cereb Cortex. 2018;28:3673–84.PubMedPubMedCentralCrossRef
36.
37.
38.
Goebbels S, Bormuth I, Bode U, Hermanson O, Schwab MH, Nave KA. Genetic targeting of principal neurons in neocortex and hippocampus of NEX-Cre mice. Genesis. 2006;44:611–21.PubMedCrossRef
39.
Hicks AN, Lorenzetti D, Gilley J, Lu B, Andersson KE, Miligan C, Overbeek PA, Oppenheim R, Bishop CE. Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) regulates axon integrity in the mouse embryo. PLoS ONE. 2012;7:e47869.PubMedPubMedCentralCrossRef
40.
Kim Y, Zhou P, Qian L, Chuang JZ, Lee J, Li C, Iadecola C, Nathan C, Ding A. MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival. J Exp Med. 2007;204:2063–74.PubMedPubMedCentralCrossRef
41.
Chou AH, Yeh TH, Ouyang P, Chen YL, Chen SY, Wang HL. Polyglutamine-expanded ataxin-3 causes cerebellar dysfunction of SCA3 transgenic mice by inducing transcriptional dysregulation. Neurobiol Dis. 2008;31:89–101.PubMedCrossRef
42.
Lieu CA, Chinta SJ, Rane A, Andersen JK. Age-related behavioral phenotype of an astrocytic monoamine oxidase-B transgenic mouse model of Parkinson’s disease. PLoS ONE. 2013;8:e54200.PubMedPubMedCentralCrossRef
43.
Wang X, Zhang Q, Bao R, Zhang N, Wang Y, Polo-Parada L, Tarim A, Alemifar A, Han X, Wilkins HM, et al. Deletion of Nampt in Projection Neurons of Adult Mice Leads to Motor Dysfunction, Neurodegeneration, and Death. Cell Rep. 2017;20:2184–200.PubMedPubMedCentralCrossRef
44.
Guyenet SJ, Furrer SA, Damian VM, Baughan TD, La Spada AR, Garden GA: A simple composite phenotype scoring system for evaluating mouse models of cerebellar ataxia. J Vis Exp 2010.
45.
Currinn H, Guscott B, Balklava Z, Rothnie A, Wassmer T. APP controls the formation of PI(3,5)P(2) vesicles through its binding of the PIKfyve complex. Cell Mol Life Sci. 2016;73:393–408.PubMedCrossRef
46.
Galiano MR, Jha S, Ho TS, Zhang C, Ogawa Y, Chang KJ, Stankewich MC, Mohler PJ, Rasband MN. A distal axonal cytoskeleton forms an intra-axonal boundary that controls axon initial segment assembly. Cell. 2012;149:1125–39.PubMedPubMedCentralCrossRef
47.
Kitay BM, McCormack R, Wang Y, Tsoulfas P, Zhai RG. Mislocalization of neuronal mitochondria reveals regulation of Wallerian degeneration and NMNAT/WLD(S)-mediated axon protection independent of axonal mitochondria. Hum Mol Genet. 2013;22:1601–14.PubMedPubMedCentralCrossRef
48.
Zhao Y, Hu Q, Cheng F, Su N, Wang A, Zou Y, Hu H, Chen X, Zhou HM, Huang X, et al. SoNar, a Highly Responsive NAD+/NADH Sensor, Allows High-Throughput Metabolic Screening of Anti-tumor Agents. Cell Metab. 2015;21:777–89.PubMedPubMedCentralCrossRef
49.
Cambronne XA, Stewart ML, Kim D, Jones-Brunette AM, Morgan RK, Farrens DL, Cohen MS, Goodman RH. Biosensor reveals multiple sources for mitochondrial NAD(+). Science. 2016;352:1474–7.PubMedPubMedCentralCrossRef
50.
Fletcher TL, Cameron P, De Camilli P, Banker G. The distribution of synapsin I and synaptophysin in hippocampal neurons developing in culture. J Neurosci. 1991;11:1617–26.PubMedPubMedCentralCrossRef
51.
Chen CY, Lin CW, Chang CY, Jiang ST, Hsueh YP. Sarm1, a negative regulator of innate immunity, interacts with syndecan-2 and regulates neuronal morphology. J Cell Biol. 2011;193:769–84.PubMedPubMedCentralCrossRef
52.
Clements RT, Fuller LE, Kraemer KR, Radomski SA, Hunter-Chang S, Hall WC, Kalantar AA, Kraemer BR: Quantification of Neurite Degeneration with Enhanced Accuracy and Efficiency in an In Vitro Model of Parkinson's Disease. eNeuro 2022, 9.
53.
Wang CL, Zhang L, Zhou Y, Zhou J, Yang XJ, Duan SM, Xiong ZQ, Ding YQ. Activity-dependent development of callosal projections in the somatosensory cortex. J Neurosci. 2007;27:11334–42.PubMedPubMedCentralCrossRef
54.
Fame RM, MacDonald JL, Macklis JD. Development, specification, and diversity of callosal projection neurons. Trends Neurosci. 2011;34:41–50.PubMedCrossRef
55.
Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS, Goldstein LS. Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science. 2005;307:1282–8.PubMedCrossRef
56.
Fu MM, Holzbaur EL. JIP1 regulates the directionality of APP axonal transport by coordinating kinesin and dynein motors. J Cell Biol. 2013;202:495–508.PubMedPubMedCentralCrossRef
57.
Gunawardena S, Goldstein LS. Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron. 2001;32:389–401.PubMedCrossRef
58.
Kamal A, Stokin GB, Yang Z, Xia CH, Goldstein LS. Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I. Neuron. 2000;28:449–59.PubMedCrossRef
59.
Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, Beyreuther K, Fischer P, Masters CL, Price DL. Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci U S A. 1990;87:1561–5.PubMedPubMedCentralCrossRef
60.
Lazarov O, Morfini GA, Lee EB, Farah MH, Szodorai A, DeBoer SR, Koliatsos VE, Kins S, Lee VM, Wong PC, et al. Axonal transport, amyloid precursor protein, kinesin-1, and the processing apparatus: revisited. J Neurosci. 2005;25:2386–95.PubMedPubMedCentralCrossRef
61.
Wang P, Yang G, Mosier DR, Chang P, Zaidi T, Gong YD, Zhao NM, Dominguez B, Lee KF, Gan WB, Zheng H. Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2. J Neurosci. 2005;25:1219–25.PubMedPubMedCentralCrossRef
62.
Klevanski M, Herrmann U, Weyer SW, Fol R, Cartier N, Wolfer DP, Caldwell JH, Korte M, Muller UC. The APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior. J Neurosci. 2015;35:16018–33.PubMedPubMedCentralCrossRef
63.
Muller UC, Deller T, Korte M. Not just amyloid: physiological functions of the amyloid precursor protein family. Nat Rev Neurosci. 2017;18:281–98.PubMedCrossRef
64.
Wirths O, Weis J, Kayed R, Saido TC, Bayer TA. Age-dependent axonal degeneration in an Alzheimer mouse model. Neurobiol Aging. 2007;28:1689–99.PubMedCrossRef
65.
Wirths O, Weis J, Szczygielski J, Multhaup G, Bayer TA. Axonopathy in an APP/PS1 transgenic mouse model of Alzheimer’s disease. Acta Neuropathol. 2006;111:312–9.PubMedCrossRef
66.
Stone JR, Singleton RH, Povlishock JT. Antibodies to the C-terminus of the beta-amyloid precursor protein (APP): a site specific marker for the detection of traumatic axonal injury. Brain Res. 2000;871:288–302.PubMedCrossRef
67.
Hortobagyi T, Wise S, Hunt N, Cary N, Djurovic V, Fegan-Earl A, Shorrock K, Rouse D, Al-Sarraj S. Traumatic axonal damage in the brain can be detected using beta-APP immunohistochemistry within 35 min after head injury to human adults. Neuropathol Appl Neurobiol. 2007;33:226–37.PubMedCrossRef
68.
Ruhling S, Kramer F, Schmutz S, Amor S, Jiangshan Z, Schmitz C, Kipp M, Hochstrasser T. Visualization of the Breakdown of the Axonal Transport Machinery: a Comparative Ultrastructural and Immunohistochemical Approach. Mol Neurobiol. 2019;56:3984–98.PubMedCrossRef
69.
Linke R, Frotscher M. Development of the rat septohippocampal projection: tracing with DiI and electron microscopy of identified growth cones. J Comp Neurol. 1993;332:69–88.PubMedCrossRef
70.
Sheth AN, McKee ML, Bhide PG. The sequence of formation and development of corticostriate connections in mice. Dev Neurosci. 1998;20:98–112.PubMedCrossRef
71.
Niou Z, Yang S, Sri A, Rodriquez H, Gilley J, Coleman MP, Lu H-C: NMNAT2 in cortical glutamatergic neurons exerts both cell and non-cell autonomous influences to shape cortical development and to maintain neuronal health. bioRxiv 2022:2022.2002.2005.479195.
72.
Ikin AF, Annaert WG, Takei K, De Camilli P, Jahn R, Greengard P, Buxbaum JD. Alzheimer amyloid protein precursor is localized in nerve terminal preparations to Rab5-containing vesicular organelles distinct from those implicated in the synaptic vesicle pathway. J Biol Chem. 1996;271:31783–6.PubMedCrossRef
73.
Shapira M, Zhai RG, Dresbach T, Bresler T, Torres VI, Gundelfinger ED, Ziv NE, Garner CC. Unitary assembly of presynaptic active zones from Piccolo-Bassoon transport vesicles. Neuron. 2003;38:237–52.PubMedCrossRef
74.
Chiba K, Araseki M, Nozawa K, Furukori K, Araki Y, Matsushima T, Nakaya T, Hata S, Saito Y, Uchida S, et al. Quantitative analysis of APP axonal transport in neurons: role of JIP1 in enhanced APP anterograde transport. Mol Biol Cell. 2014;25:3569–80.PubMedPubMedCentralCrossRef
75.
Shiff G, Morel N. Rapid anterograde axonal transport of the syntaxin-SNAP 25-VAMP complex. J Neurochem. 1997;68:1663–7.PubMedCrossRef
76.
Cai Q, Pan PY, Sheng ZH. Syntabulin-kinesin-1 family member 5B-mediated axonal transport contributes to activity-dependent presynaptic assembly. J Neurosci. 2007;27:7284–96.PubMedPubMedCentralCrossRef
77.
Forman DS: Axonal transport of mitochondria. Axonal Transport 1987:155–163.
78.
Forman DS, Lynch KJ, Smith RS. Organelle dynamics in lobster axons: anterograde, retrograde and stationary mitochondria. Brain Res. 1987;412:96–106.PubMedCrossRef
79.
80.
Melkov A, Abdu U. Regulation of long-distance transport of mitochondria along microtubules. Cell Mol Life Sci. 2018;75:163–76.PubMedCrossRef
81.
Plucinska G, Misgeld T. Imaging of neuronal mitochondria in situ. Curr Opin Neurobiol. 2016;39:152–63.PubMedCrossRef
82.
83.
Sasaki Y. Metabolic aspects of neuronal degeneration: From a NAD(+) point of view. Neurosci Res. 2019;139:9–20.PubMedCrossRef
84.
85.
Hinckelmann MV, Virlogeux A, Niehage C, Poujol C, Choquet D, Hoflack B, Zala D, Saudou F. Self-propelling vesicles define glycolysis as the minimal energy machinery for neuronal transport. Nat Commun. 2016;7:13233.PubMedPubMedCentralCrossRef
86.
Tang Y, Scott D, Das U, Gitler D, Ganguly A, Roy S. Fast vesicle transport is required for the slow axonal transport of synapsin. J Neurosci. 2013;33:15362–75.PubMedPubMedCentralCrossRef
87.
Ikemoto A, Bole DG, Ueda T. Glycolysis and glutamate accumulation into synaptic vesicles. Role of glyceraldehyde phosphate dehydrogenase and 3-phosphoglycerate kinase. J Biol Chem. 2003;278:5929–40.PubMedCrossRef
88.
Mayer PR, Huang N, Dewey CM, Dries DR, Zhang H, Yu G. Expression, localization, and biochemical characterization of nicotinamide mononucleotide adenylyltransferase 2. J Biol Chem. 2010;285:40387–96.PubMedPubMedCentralCrossRef
89.
Guedes-Dias P, Nirschl JJ, Abreu N, Tokito MK, Janke C, Magiera MM, Holzbaur ELF. Kinesin-3 Responds to Local Microtubule Dynamics to Target Synaptic Cargo Delivery to the Presynapse. Curr Biol. 2019;29(268–282):e268.CrossRef
90.
Cunnane SC, Trushina E, Morland C, Prigione A, Casadesus G, Andrews ZB, Beal MF, Bergersen LH, Brinton RD, de la Monte S, et al. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing. Nat Rev Drug Discov. 2020;19:609–33.PubMedPubMedCentralCrossRef
91.
Alano CC, Garnier P, Ying W, Higashi Y, Kauppinen TM, Swanson RA. NAD+ depletion is necessary and sufficient for poly(ADP-ribose) polymerase-1-mediated neuronal death. J Neurosci. 2010;30:2967–78.PubMedPubMedCentralCrossRef
92.
Wang S, Xing Z, Vosler PS, Yin H, Li W, Zhang F, Signore AP, Stetler RA, Gao Y, Chen J. Cellular NAD replenishment confers marked neuroprotection against ischemic cell death: role of enhanced DNA repair. Stroke. 2008;39:2587–95.PubMedPubMedCentralCrossRef
93.
Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J. The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD(+) Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron. 2017;93(1334–1343):e1335.
94.
Angeletti C, Amici A, Gilley J, Loreto A, Trapanotto AG, Antoniou C, Merlini E, Coleman MP, Orsomando G. SARM1 is a multi-functional NAD(P)ase with prominent base exchange activity, all regulated by multiple physiologically relevant NAD metabolites. iScience. 2022;25:103812.PubMedPubMedCentralCrossRef
95.
Figley MD, Gu W, Nanson JD, Shi Y, Sasaki Y, Cunnea K, Malde AK, Jia X, Luo Z, Saikot FK, et al. SARM1 is a metabolic sensor activated by an increased NMN/NAD(+) ratio to trigger axon degeneration. Neuron. 2021;109(1118–1136):e1111.
96.
Di Stefano M, Nascimento-Ferreira I, Orsomando G, Mori V, Gilley J, Brown R, Janeckova L, Vargas ME, Worrell LA, Loreto A, et al. A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration. Cell Death Differ. 2015;22:731–42.PubMedCrossRef
97.
Gilley J, Orsomando G, Nascimento-Ferreira I, Coleman MP. Absence of SARM1 rescues development and survival of NMNAT2-deficient axons. Cell Rep. 2015;10:1974–81.PubMedPubMedCentralCrossRef
98.
Gilley J, Ribchester RR, Coleman MP. Sarm1 Deletion, but Not WldS, Confers Lifelong Rescue in a Mouse Model of Severe Axonopathy. Cell Rep. 2017;21:10–6.PubMedPubMedCentralCrossRef
99.
Ashrafi G, de Juan-Sanz J, Farrell RJ, Ryan TA. Molecular Tuning of the Axonal Mitochondrial Ca(2+) Uniporter Ensures Metabolic Flexibility of Neurotransmission. Neuron. 2020;105(678–687):e675.
100.
Osterloh JM, Yang J, Rooney TM, Fox AN, Adalbert R, Powell EH, Sheehan AE, Avery MA, Hackett R, Logan MA, et al. dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science. 2012;337:481–4.PubMedPubMedCentralCrossRef
101.
Ko KW, Devault L, Sasaki Y, Milbrandt J, DiAntonio A: Live imaging reveals the cellular events downstream of SARM1 activation. Elife 2021, 10.
102.
103.
Li Y, Pazyra-Murphy MF, Avizonis D, de Sa Tavares Russo M, Tang S, Chen CY, Hsueh YP, Bergholz JS, Jiang T, Zhao JJ, et al: Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN. J Cell Biol 2022, 221.
104.
Bellon A, Mann F. Keeping up with advances in axon guidance. Curr Opin Neurobiol. 2018;53:183–91.PubMedCrossRef
105.
Ketschek A, Sainath R, Holland S, Gallo G. The Axonal Glycolytic Pathway Contributes to Sensory Axon Extension and Growth Cone Dynamics. J Neurosci. 2021;41:6637–51.PubMedPubMedCentralCrossRef
106.
Ketschek A, Holland SM, Gallo G. SARM1 Suppresses Axon Branching Through Attenuation of Axonal Cytoskeletal Dynamics. Front Mol Neurosci. 2022;15:726962.PubMedPubMedCentralCrossRef
107.
Izadifar A, Courchet J, Virga DM, Verreet T, Hamilton S, Ayaz D, Misbaer A, Vandenbogaerde S, Monteiro L, Petrovic M, et al. Axon morphogenesis and maintenance require an evolutionary conserved safeguard function of Wnk kinases antagonizing Sarm and Axed. Neuron. 2021;109(2864–2883):e2868.
108.
Turner NL, Macrina T, Bae JA, Yang R, Wilson AM, Schneider-Mizell C, Lee K, Lu R, Wu J, Bodor AL, et al: Multiscale and multimodal reconstruction of cortical structure and function. bioRxiv 2020:2020.2010.2014.338681.
109.
Lewis TL Jr, Turi GF, Kwon SK, Losonczy A, Polleux F. Progressive Decrease of Mitochondrial Motility during Maturation of Cortical Axons In Vitro and In Vivo. Curr Biol. 2016;26:2602–8.PubMedPubMedCentralCrossRef
110.
Moutaux E, Christaller W, Scaramuzzino C, Genoux A, Charlot B, Cazorla M, Saudou F. Neuronal network maturation differently affects secretory vesicles and mitochondria transport in axons. Sci Rep. 2018;8:13429.PubMedPubMedCentralCrossRef
111.
Zhou B, Yu P, Lin MY, Sun T, Chen Y, Sheng ZH. Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits. J Cell Biol. 2016;214:103–19.PubMedPubMedCentralCrossRef
112.
Cagin U, Duncan OF, Gatt AP, Dionne MS, Sweeney ST, Bateman JM. Mitochondrial retrograde signaling regulates neuronal function. Proc Natl Acad Sci U S A. 2015;112:E6000–6009.PubMedPubMedCentralCrossRef
113.
Ibanez CF. Message in a bottle: long-range retrograde signaling in the nervous system. Trends Cell Biol. 2007;17:519–28.PubMedCrossRef
114.
Das U, Scott DA, Ganguly A, Koo EH, Tang Y, Roy S. Activity-induced convergence of APP and BACE-1 in acidic microdomains via an endocytosis-dependent pathway. Neuron. 2013;79:447–60.PubMedPubMedCentralCrossRef
115.
Chidlow G, Ebneter A, Wood JP, Casson RJ. The optic nerve head is the site of axonal transport disruption, axonal cytoskeleton damage and putative axonal regeneration failure in a rat model of glaucoma. Acta Neuropathol. 2011;121:737–51.PubMedPubMedCentralCrossRef
116.
Burke S, Trudeau LE: Axonal Domain Structure as a Putative Identifier of Neuron-Specific Vulnerability to Oxidative Stress in Cultured Neurons. eNeuro 2022, 9.
117.
Giguere N, Delignat-Lavaud B, Herborg F, Voisin A, Li Y, Jacquemet V, Anand-Srivastava M, Gether U, Giros B, Trudeau LE. Increased vulnerability of nigral dopamine neurons after expansion of their axonal arborization size through D2 dopamine receptor conditional knockout. PLoS Genet. 2019;15:e1008352.PubMedPubMedCentralCrossRef
118.
Guo W, Stoklund Dittlau K, Van Den Bosch L. Axonal transport defects and neurodegeneration: Molecular mechanisms and therapeutic implications. Semin Cell Dev Biol. 2020;99:133–50.PubMedCrossRef
119.
Baleriola J, Walker CA, Jean YY, Crary JF, Troy CM, Nagy PL, Hengst U. Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions. Cell. 2014;158:1159–72.PubMedPubMedCentralCrossRef
120.
Lamberts JT, Hildebrandt EN, Brundin P. Spreading of alpha-synuclein in the face of axonal transport deficits in Parkinson’s disease: a speculative synthesis. Neurobiol Dis. 2015;77:276–83.PubMedCrossRef
121.
122.
Ji H, Sapar ML, Sarkar A, Wang B, Han C: Phagocytosis and self-destruction break down dendrites of Drosophila sensory neurons at distinct steps of Wallerian degeneration. Proc Natl Acad Sci U S A 2022, 119.
123.
124.
Zampese E, Wokosin DL, Gonzalez-Rodriguez P, Guzman JN, Tkatch T, Kondapalli J, Surmeier WC, D’Alessandro KB, De Stefani D, Rizzuto R, et al. Ca(2+) channels couple spiking to mitochondrial metabolism in substantia nigra dopaminergic neurons. Sci Adv. 2022;8:eabp8701.PubMedPubMedCentralCrossRef
125.
Perez-Liebana I, Juaristi I, Gonzalez-Sanchez P, Gonzalez-Moreno L, Rial E, Podunavac M, Zakarian A, Molgo J, Vallejo-Illarramendi A, Mosqueira-Martin L, et al. A Ca(2+)-Dependent Mechanism Boosting Glycolysis and OXPHOS by Activating Aralar-Malate-Aspartate Shuttle, upon Neuronal Stimulation. J Neurosci. 2022;42:3879–95.PubMedPubMedCentralCrossRef
126.
Yu SB, Sanchez RG, Papich ZD, Whisenant TC, Ghassemian M, Koberstein JN, Stewart ML, Pekkurnaz G: Neuronal activity-driven O-GlcNAcylation promotes mitochondrial plasticity. bioRxiv 2023:2023.2001.2011.523512.
127.
Pekkurnaz G, Trinidad JC, Wang X, Kong D, Schwarz TL. Glucose regulates mitochondrial motility via Milton modification by O-GlcNAc transferase. Cell. 2014;158:54–68.PubMedPubMedCentralCrossRef
128.
Li H, Guglielmetti C, Sei YJ, Zilberter M, Le Page LM, Shields L, Yang J, Nguyen K, Tiret B, Gao X, et al. Neurons require glucose uptake and glycolysis in vivo. Cell Rep. 2023;42:112335.PubMedPubMedCentralCrossRef
129.
Mor DE, Sohrabi S, Kaletsky R, Keyes W, Tartici A, Kalia V, Miller GW, Murphy CT. Metformin rescues Parkinson’s disease phenotypes caused by hyperactive mitochondria. Proc Natl Acad Sci U S A. 2020;117:26438–47.PubMedPubMedCentralCrossRef
130.
Soman SK, Bazala M, Keatinge M, Bandmann O, Kuznicki J: Restriction of mitochondrial calcium overload by mcu inactivation renders a neuroprotective effect in zebrafish models of Parkinson's disease. Biol Open 2019, 8.
131.
Calvo-Rodriguez M, Hou SS, Snyder AC, Kharitonova EK, Russ AN, Das S, Fan Z, Muzikansky A, Garcia-Alloza M, Serrano-Pozo A, et al. Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer’s disease. Nat Commun. 2020;11:2146.PubMedPubMedCentralCrossRef
132.
133.
Gerdts J, Summers DW, Sasaki Y, DiAntonio A, Milbrandt J. Sarm1-mediated axon degeneration requires both SAM and TIR interactions. J Neurosci. 2013;33:13569–80.PubMedPubMedCentralCrossRef
134.
Murata H, Khine CC, Nishikawa A, Yamamoto KI, Kinoshita R, Sakaguchi M. c-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD(+) cleavage activity to inhibit mitochondrial respiration. J Biol Chem. 2018;293:18933–43.PubMedPubMedCentralCrossRef
135.
Sato-Yamada Y, Strickland A, Sasaki Y, Bloom J, DiAntonio A, Milbrandt J: A SARM1-mitochondrial feedback loop drives neuropathogenesis in a Charcot-Marie-Tooth disease type 2A rat model. J Clin Invest 2022, 132.
136.
Reiman EM, Caselli RJ, Yun LS, Chen K, Bandy D, Minoshima S, Thibodeau SN, Osborne D. Preclinical evidence of Alzheimer’s disease in persons homozygous for the ε4 allele for apolipoprotein E. J New Engl J Med. 1996;334:752–8.PubMedCrossRef
137.
Ye F, Funk Q, Rockers E, Shulman JM, Masdeu JC, Pascual B. Alzheimer’s Disease Neuroimaging I: In Alzheimer-prone brain regions, metabolism and risk-gene expression are strongly correlated. Brain Commun. 2022;4:fcac216.PubMedPubMedCentralCrossRef
138.
Ciarmiello A, Cannella M, Lastoria S, Simonelli M, Frati L, Rubinsztein DC, Squitieri F. Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington’s disease. J Nucl Med. 2006;47:215–22.PubMed
139.
Diehl-Schmid J, Licata A, Goldhardt O, Forstl H, Yakushew I, Otto M, Anderl-Straub S, Beer A, Ludolph AC, Landwehrmeyer GB, et al. FDG-PET underscores the key role of the thalamus in frontotemporal lobar degeneration caused by C9ORF72 mutations. Transl Psychiatry. 2019;9:54.PubMedPubMedCentralCrossRef
140.
Cistaro A, Valentini MC, Chio A, Nobili F, Calvo A, Moglia C, Montuschi A, Morbelli S, Salmaso D, Fania P, et al. Brain hypermetabolism in amyotrophic lateral sclerosis: a FDG PET study in ALS of spinal and bulbar onset. Eur J Nucl Med Mol Imaging. 2012;39:251–9.PubMedCrossRef
141.
Matthews DC, Lerman H, Lukic A, Andrews RD, Mirelman A, Wernick MN, Giladi N, Strother SC, Evans KC, Cedarbaum JM, Even-Sapir E. FDG PET Parkinson’s disease-related pattern as a biomarker for clinical trials in early stage disease. Neuroimage Clin. 2018;20:572–9.PubMedPubMedCentralCrossRef
142.
Kalpouzos G, Chetelat G, Baron JC, Landeau B, Mevel K, Godeau C, Barre L, Constans JM, Viader F, Eustache F, Desgranges B. Voxel-based mapping of brain gray matter volume and glucose metabolism profiles in normal aging. Neurobiol Aging. 2009;30:112–24.PubMedCrossRef
143.
Oh H, Madison C, Baker S, Rabinovici G, Jagust W. Dynamic relationships between age, amyloid-beta deposition, and glucose metabolism link to the regional vulnerability to Alzheimer’s disease. Brain. 2016;139:2275–89.PubMedPubMedCentralCrossRef
144.
Krell-Roesch J, Syrjanen JA, Vassilaki M, Lowe VJ, Vemuri P, Mielke MM, Machulda MM, Stokin GB, Christianson TJ, Kremers WK, et al. Brain Regional Glucose Metabolism, Neuropsychiatric Symptoms, and the Risk of Incident Mild Cognitive Impairment: The Mayo Clinic Study of Aging. Am J Geriatr Psychiatry. 2021;29:179–91.PubMedCrossRef
145.
Baran TM, Lin FV. Alzheimer’s Disease Neuroimaging I: Amyloid and FDG PET of Successful Cognitive Aging: Global and Cingulate-Specific Differences. J Alzheimers Dis. 2018;66:307–18.PubMedPubMedCentralCrossRef
146.
Kelley CM, Ginsberg SD, Liang WS, Counts SE, Mufson EJ. Posterior cingulate cortex reveals an expression profile of resilience in cognitively intact elders. Brain Commun. 2022;4:fcac162.PubMedPubMedCentralCrossRef
147.
Leech R, Sharp DJ. The role of the posterior cingulate cortex in cognition and disease. Brain. 2014;137:12–32.PubMedCrossRef
148.
Crossley NA, Mechelli A, Scott J, Carletti F, Fox PT, McGuire P, Bullmore ET. The hubs of the human connectome are generally implicated in the anatomy of brain disorders. Brain. 2014;137:2382–95.PubMedPubMedCentralCrossRef
149.
150.
Hagmann P, Cammoun L, Gigandet X, Meuli R, Honey CJ, Wedeen VJ, Sporns O. Mapping the structural core of human cerebral cortex. PLoS Biol. 2008;6:e159.PubMedPubMedCentralCrossRef
151.
Mito R, Raffelt D, Dhollander T, Vaughan DN, Tournier JD, Salvado O, Brodtmann A, Rowe CC, Villemagne VL, Connelly A. Fibre-specific white matter reductions in Alzheimer’s disease and mild cognitive impairment. Brain. 2018;141:888–902.PubMedCrossRef
152.
Xu Z, Xia M, Wang X, Liao X, Zhao T, He Y. Meta-connectomic analysis maps consistent, reproducible, and transcriptionally relevant functional connectome hubs in the human brain. Commun Biol. 2022;5:1056.PubMedPubMedCentralCrossRef
153.
Goyal MS, Vlassenko AG, Blazey TM, Su Y, Couture LE, Durbin TJ, Bateman RJ, Benzinger TL, Morris JC, Raichle ME. Loss of Brain Aerobic Glycolysis in Normal Human Aging. Cell Metab. 2017;26(353–360):e353.CrossRef
154.
Vlassenko AG, Gordon BA, Goyal MS, Su Y, Blazey TM, Durbin TJ, Couture LE, Christensen JJ, Jafri H, Morris JC, et al. Aerobic glycolysis and tau deposition in preclinical Alzheimer’s disease. Neurobiol Aging. 2018;67:95–8.PubMedPubMedCentralCrossRef
155.
Goyal MS, Blazey T, Metcalf NV, McAvoy MP, Strain J, Rahmani M, Durbin TJ, Xiong C, Benzinger TL-S, Morris JC, et al: Brain aerobic glycolysis and resilience in Alzheimer disease. bioRxiv 2022:2022.2006.2021.497006.
156.
Hou Y, Wei Y, Lautrup S, Yang B, Wang Y, Cordonnier S, Mattson MP, Croteau DL, Bohr VA: NAD(+) supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer's disease via cGAS-STING. Proc Natl Acad Sci U S A 2021, 118.
157.
Harlan BA, Killoy KM, Pehar M, Liu L, Auwerx J, Vargas MR. Evaluation of the NAD(+) biosynthetic pathway in ALS patients and effect of modulating NAD(+) levels in hSOD1-linked ALS mouse models. Exp Neurol. 2020;327:113219.PubMedPubMedCentralCrossRef
158.
Gautam M, Gunay A, Chandel NS, Ozdinler PH. Mitochondrial dysregulation occurs early in ALS motor cortex with TDP-43 pathology and suggests maintaining NAD(+) balance as a therapeutic strategy. Sci Rep. 2022;12:4287.PubMedPubMedCentralCrossRef
159.
Ljungberg MC, Ali YO, Zhu J, Wu CS, Oka K, Zhai RG, Lu HC. CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy. Hum Mol Genet. 2012;21:251–67.PubMedCrossRef
160.
Cheng XS, Shi FX, Zhao KP, Lin W, Li XY, Zhang J, Bu YY, Zhu R, Li XH, Duan DX, et al. Nmnat2 attenuates amyloidogenesis and up-regulates ADAM10 in AMPK activity-dependent manner. Aging (Albany NY). 2021;13:23620–36.PubMedCrossRef
161.
Fang F, Zhuang P, Feng X, Liu P, Liu D, Huang H, Li L, Chen W, Liu L, Sun Y, et al. NMNAT2 is downregulated in glaucomatous RGCs, and RGC-specific gene therapy rescues neurodegeneration and visual function. Mol Ther. 2022;30:1421–31.PubMedPubMedCentralCrossRef
162.
Ren MYY, Heng KHY, Ng LY, Chong CY, Ng YT, Gorur-Shandilya S, Lee RMQ, Lim KL, Zhang J, Koh TW. MED13 and glycolysis are conserved modifiers of α-synuclein-associated neurodegeneration. Cell Report. 2022;41(12):111852.CrossRef
163.
Manzo E, Lorenzini I, Barrameda D, O'Conner AG, Barrows JM, Starr A, Kovalik T, Rabichow BE, Lehmkuhl EM, Shreiner DD, et al: Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS. Elife 2019, 8.
Metadata
Title
NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport
Authors
Sen Yang
Zhen-Xian Niou
Andrea Enriquez
Jacob LaMar
Jui-Yen Huang
Karen Ling
Paymaan Jafar-Nejad
Jonathan Gilley
Michael P. Coleman
Jason M. Tennessen
Vidhya Rangaraju
Hui-Chen Lu
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2024
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-023-00690-9

Other articles of this Issue 1/2024

Molecular Neurodegeneration 1/2024 Go to the issue

Review

Updates on mouse models of Alzheimer’s disease

Review

Fluid biomarkers for amyotrophic lateral sclerosis: a review

Research article

Regulation of human microglial gene expression and function via RNAase-H active antisense oligonucleotides in vivo in Alzheimer’s disease

Review

The endotoxin hypothesis of Alzheimer’s disease

Correction

Correction: Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade

Research article

Cognitive, functional, and neuropsychiatric correlates of regional tau pathology in autopsy-confirmed chronic traumatic encephalopathy