SARM1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotides
SARM1 is a key regulator of a conserved program of axon degeneration increasingly linked to human neurodegenerative diseases. Pathological SARM1 activation causes rapid NAD consumption, disrupting cellular homeostasis and leading to axon degeneration. In this study, we develop antisense oligonucleot...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-09-01
|
| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125002025 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849714558073044992 |
|---|---|
| author | Andrea Loreto Kaitlyn M.L. Cramb Lucy A. McDermott Christina Antoniou Ilenia Cirilli Maria Claudia Caiazza Elisa Merlini Peter Arthur-Farraj W. Daniel du Preez Elliot D. Mock Hien T. Zhao David L. Bennett Giuseppe Orsomando Michael P. Coleman Richard Wade-Martins |
| author_facet | Andrea Loreto Kaitlyn M.L. Cramb Lucy A. McDermott Christina Antoniou Ilenia Cirilli Maria Claudia Caiazza Elisa Merlini Peter Arthur-Farraj W. Daniel du Preez Elliot D. Mock Hien T. Zhao David L. Bennett Giuseppe Orsomando Michael P. Coleman Richard Wade-Martins |
| author_sort | Andrea Loreto |
| collection | DOAJ |
| description | SARM1 is a key regulator of a conserved program of axon degeneration increasingly linked to human neurodegenerative diseases. Pathological SARM1 activation causes rapid NAD consumption, disrupting cellular homeostasis and leading to axon degeneration. In this study, we develop antisense oligonucleotides (ASOs) targeting human SARM1, demonstrating robust neuroprotection against morphological, metabolic, and mitochondrial impairment in human iPSC-derived dopamine neurons induced by the lethal neurotoxin vacor, a potent SARM1 activator. Furthermore, our findings reveal that axon fragmentation can be prevented, and mitochondrial dysfunction reversed using the NAD precursor nicotinamide, a form of vitamin B3, even after SARM1 activation has occurred, when neurons are already unhealthy. This research identifies ASOs as a promising therapeutic strategy to block SARM1, and provides an extensive characterisation and further mechanistic insights that demonstrate the reversibility of SARM1 toxicity in human neurons. It also identifies the SARM1 activator vacor as a specific and reversible neuroablative agent in human neurons. |
| format | Article |
| id | doaj-art-e7b0c5154f0f43d38d085e503fc5ade5 |
| institution | DOAJ |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-e7b0c5154f0f43d38d085e503fc5ade52025-08-20T03:13:40ZengElsevierNeurobiology of Disease1095-953X2025-09-0121310698610.1016/j.nbd.2025.106986SARM1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotidesAndrea Loreto0Kaitlyn M.L. Cramb1Lucy A. McDermott2Christina Antoniou3Ilenia Cirilli4Maria Claudia Caiazza5Elisa Merlini6Peter Arthur-Farraj7W. Daniel du Preez8Elliot D. Mock9Hien T. Zhao10David L. Bennett11Giuseppe Orsomando12Michael P. Coleman13Richard Wade-Martins14Neuroscience, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Save Sight Institute, Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Oxford Parkinson's Disease Centre and Department of Physiology, Anatomy & Genetics, Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UK; John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UK; Corresponding author at: Neuroscience, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.Oxford Parkinson's Disease Centre and Department of Physiology, Anatomy & Genetics, Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UK; Corresponding authors.Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UKJohn van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UKDepartment of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, Ancona 60131, ItalyOxford Parkinson's Disease Centre and Department of Physiology, Anatomy & Genetics, Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UKNeuroscience, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney, Australia; John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UKJohn van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UK; Blizard Institute, Barts and London School of Medicine and Dentistry, Queen Mary University London, UKSave Sight Institute, Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney, AustraliaOxford Parkinson's Disease Centre and Department of Physiology, Anatomy & Genetics, Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UKNeuroscience Drug Discovery, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USANuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UKDepartment of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, Ancona 60131, ItalyJohn van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UK; Corresponding authors.Oxford Parkinson's Disease Centre and Department of Physiology, Anatomy & Genetics, Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UK; Corresponding authors.SARM1 is a key regulator of a conserved program of axon degeneration increasingly linked to human neurodegenerative diseases. Pathological SARM1 activation causes rapid NAD consumption, disrupting cellular homeostasis and leading to axon degeneration. In this study, we develop antisense oligonucleotides (ASOs) targeting human SARM1, demonstrating robust neuroprotection against morphological, metabolic, and mitochondrial impairment in human iPSC-derived dopamine neurons induced by the lethal neurotoxin vacor, a potent SARM1 activator. Furthermore, our findings reveal that axon fragmentation can be prevented, and mitochondrial dysfunction reversed using the NAD precursor nicotinamide, a form of vitamin B3, even after SARM1 activation has occurred, when neurons are already unhealthy. This research identifies ASOs as a promising therapeutic strategy to block SARM1, and provides an extensive characterisation and further mechanistic insights that demonstrate the reversibility of SARM1 toxicity in human neurons. It also identifies the SARM1 activator vacor as a specific and reversible neuroablative agent in human neurons.http://www.sciencedirect.com/science/article/pii/S0969996125002025SARM1VacorASONicotinamideAxon degenerationMitochondrial dysfunction |
| spellingShingle | Andrea Loreto Kaitlyn M.L. Cramb Lucy A. McDermott Christina Antoniou Ilenia Cirilli Maria Claudia Caiazza Elisa Merlini Peter Arthur-Farraj W. Daniel du Preez Elliot D. Mock Hien T. Zhao David L. Bennett Giuseppe Orsomando Michael P. Coleman Richard Wade-Martins SARM1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotides Neurobiology of Disease SARM1 Vacor ASO Nicotinamide Axon degeneration Mitochondrial dysfunction |
| title | SARM1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotides |
| title_full | SARM1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotides |
| title_fullStr | SARM1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotides |
| title_full_unstemmed | SARM1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotides |
| title_short | SARM1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotides |
| title_sort | sarm1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotides |
| topic | SARM1 Vacor ASO Nicotinamide Axon degeneration Mitochondrial dysfunction |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125002025 |
| work_keys_str_mv | AT andrealoreto sarm1activationinducesreversiblemitochondrialdysfunctionandcanbepreventedinhumanneuronsbyantisenseoligonucleotides AT kaitlynmlcramb sarm1activationinducesreversiblemitochondrialdysfunctionandcanbepreventedinhumanneuronsbyantisenseoligonucleotides AT lucyamcdermott sarm1activationinducesreversiblemitochondrialdysfunctionandcanbepreventedinhumanneuronsbyantisenseoligonucleotides AT christinaantoniou sarm1activationinducesreversiblemitochondrialdysfunctionandcanbepreventedinhumanneuronsbyantisenseoligonucleotides AT ileniacirilli sarm1activationinducesreversiblemitochondrialdysfunctionandcanbepreventedinhumanneuronsbyantisenseoligonucleotides AT mariaclaudiacaiazza sarm1activationinducesreversiblemitochondrialdysfunctionandcanbepreventedinhumanneuronsbyantisenseoligonucleotides AT elisamerlini sarm1activationinducesreversiblemitochondrialdysfunctionandcanbepreventedinhumanneuronsbyantisenseoligonucleotides AT peterarthurfarraj sarm1activationinducesreversiblemitochondrialdysfunctionandcanbepreventedinhumanneuronsbyantisenseoligonucleotides AT wdanieldupreez sarm1activationinducesreversiblemitochondrialdysfunctionandcanbepreventedinhumanneuronsbyantisenseoligonucleotides AT elliotdmock sarm1activationinducesreversiblemitochondrialdysfunctionandcanbepreventedinhumanneuronsbyantisenseoligonucleotides AT hientzhao sarm1activationinducesreversiblemitochondrialdysfunctionandcanbepreventedinhumanneuronsbyantisenseoligonucleotides AT davidlbennett sarm1activationinducesreversiblemitochondrialdysfunctionandcanbepreventedinhumanneuronsbyantisenseoligonucleotides AT giuseppeorsomando sarm1activationinducesreversiblemitochondrialdysfunctionandcanbepreventedinhumanneuronsbyantisenseoligonucleotides AT michaelpcoleman sarm1activationinducesreversiblemitochondrialdysfunctionandcanbepreventedinhumanneuronsbyantisenseoligonucleotides AT richardwademartins sarm1activationinducesreversiblemitochondrialdysfunctionandcanbepreventedinhumanneuronsbyantisenseoligonucleotides |