NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport
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 n...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-01-01
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| Series: | Molecular Neurodegeneration |
| Online Access: | https://doi.org/10.1186/s13024-023-00690-9 |
| _version_ | 1797273268510523392 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Sen Yang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T14:41:04Z |
| format | Article |
| id | doaj.art-b4cc4bd0d6814ca5997b7215a718255b |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-03-07T14:41:04Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-b4cc4bd0d6814ca5997b7215a718255b2024-03-05T20:21:13ZengBMCMolecular Neurodegeneration1750-13262024-01-0119113110.1186/s13024-023-00690-9NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transportSen Yang0Zhen-Xian Niou1Andrea Enriquez2Jacob LaMar3Jui-Yen Huang4Karen Ling5Paymaan Jafar-Nejad6Jonathan Gilley7Michael P. Coleman8Jason M. Tennessen9Vidhya Rangaraju10Hui-Chen Lu11The Linda and Jack Gill Center for Biomolecular Sciences, Indiana UniversityThe Linda and Jack Gill Center for Biomolecular Sciences, Indiana UniversityThe Linda and Jack Gill Center for Biomolecular Sciences, Indiana UniversityThe Linda and Jack Gill Center for Biomolecular Sciences, Indiana UniversityThe Linda and Jack Gill Center for Biomolecular Sciences, Indiana UniversityNeuroscience Drug Discovery, Ionis Pharmaceuticals, Inc., 2855, Gazelle CourtNeuroscience Drug Discovery, Ionis Pharmaceuticals, Inc., 2855, Gazelle CourtDepartment of Clinical Neuroscience, Cambridge UniversityDepartment of Clinical Neuroscience, Cambridge UniversityDepartment of Biology, Indiana UniversityMax Planck Florida Institute for NeuroscienceThe Linda and Jack Gill Center for Biomolecular Sciences, Indiana UniversityAbstract 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.https://doi.org/10.1186/s13024-023-00690-9 |
| spellingShingle | 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 NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport Molecular Neurodegeneration |
| title | NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport |
| title_full | NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport |
| title_fullStr | NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport |
| title_full_unstemmed | NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport |
| title_short | NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport |
| title_sort | nmnat2 supports vesicular glycolysis via nad homeostasis to fuel fast axonal transport |
| url | https://doi.org/10.1186/s13024-023-00690-9 |
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