Nusinersen corrects L-arginine deficiency in the cerebrospinal fluid of patients with severe spinal muscular atrophy
Spinal Muscular Atrophy (SMA) is a progressive neuromuscular disorder caused by homozygous loss of the survival motor neuron 1 (SMN1) gene, leading to reduced SMN protein expression. Increasing evidence implicates neurotransmission deficits in the pathophysiology of SMA. In particular, alterations i...
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Elsevier
2025-10-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125002621 |
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| author | Amber Hassan Raffaella di Vito Anna Caretto Tommaso Nuzzo Adele D'Amico Chiara Panicucci Claudio Bruno Enrico Bertini Alessandro Vercelli Marina Boido Francesco Errico Livio Pellizzoni Alessandro Usiello |
| author_facet | Amber Hassan Raffaella di Vito Anna Caretto Tommaso Nuzzo Adele D'Amico Chiara Panicucci Claudio Bruno Enrico Bertini Alessandro Vercelli Marina Boido Francesco Errico Livio Pellizzoni Alessandro Usiello |
| author_sort | Amber Hassan |
| collection | DOAJ |
| description | Spinal Muscular Atrophy (SMA) is a progressive neuromuscular disorder caused by homozygous loss of the survival motor neuron 1 (SMN1) gene, leading to reduced SMN protein expression. Increasing evidence implicates neurotransmission deficits in the pathophysiology of SMA. In particular, alterations in neuroactive amino acids involved in glutamatergic neurotransmission have recently been identified in both the cerebrospinal fluid (CSF) of SMApatients and the spinal cord of SMNΔ7 mouse models. L-arginine, a precursor of nitric oxide, plays a critical role in glutamatergic receptor signalling, influencing neurotransmitter release, synaptic plasticity, and neuroprotection. However, it remains unclear whether SMN deficiency affects L-arginine metabolism in SMA. To address this, we used high-performance liquid chromatography to investigate whether SMN deficiency alters L-arginine homeostasis in the central nervous system of SMNΔ7 mice and in the CSF of SMA patients with varying disease severity, both before and after treatment with the SMN-inducing therapy Nusinersen. Notably, we observed significantly reduced L-arginine levels in the brainstem and spinal cord of symptomatic SMA mice compared to age-matched wild-type littermates. Consistent with these findings, we revealed lower L-arginine levels in severe SMA1 patients compared to milder SMA2 and SMA3 patients and healthy controls, enhancing the translational strength of our findings. Importantly, Nusinersen-mediated SMN upregulation fully restored L-arginine homeostasis in the CSF of severe SMA1 patients. In conclusion, our results demonstrate a dysregulation of L-arginine in SMA and highlight a role for SMN-enhancing therapies in restoring neurochemical alterations observed in patients with this neurodegenerative disease. |
| format | Article |
| id | doaj-art-bf4ae7152a1d4a40932c4435aa236dfd |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-bf4ae7152a1d4a40932c4435aa236dfd2025-08-20T04:00:27ZengElsevierNeurobiology of Disease1095-953X2025-10-0121410704610.1016/j.nbd.2025.107046Nusinersen corrects L-arginine deficiency in the cerebrospinal fluid of patients with severe spinal muscular atrophyAmber Hassan0Raffaella di Vito1Anna Caretto2Tommaso Nuzzo3Adele D'Amico4Chiara Panicucci5Claudio Bruno6Enrico Bertini7Alessandro Vercelli8Marina Boido9Francesco Errico10Livio Pellizzoni11Alessandro Usiello12Laboratory of Translational Neuroscience, Ceinge Biotecnologie Avanzate “Franco Salvatore”, 80145 Naples, Italy; European School of Molecular Medicine, University of Milan, 20122 Milan, ItalyLaboratory of Translational Neuroscience, Ceinge Biotecnologie Avanzate “Franco Salvatore”, 80145 Naples, Italy; Department of Environmental, Biological and Pharmaceutical Science and Technologies, University of Campania ''Luigi Vanvitelli'', 81100 Caserta, ItalyDepartment of Neuroscience Rita Levi-Montalcini, University of Turin, 10126 Turin, Italy; Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano (TO), ItalyLaboratory of Translational Neuroscience, Ceinge Biotecnologie Avanzate “Franco Salvatore”, 80145 Naples, Italy; Department of Environmental, Biological and Pharmaceutical Science and Technologies, University of Campania ''Luigi Vanvitelli'', 81100 Caserta, ItalyUnit of Muscular and Neurodegenerative Disorders, Bambino Gesu' Children's Hospital IRCCS, 00165 Roma, ItalyCenter of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, 16147 Genova, ItalyCenter of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal, and Child Health - DINOGMI, University of Genova, 16132 Genova, ItalyUnit of Muscular and Neurodegenerative Disorders, Bambino Gesu' Children's Hospital IRCCS, 00165 Roma, ItalyDepartment of Neuroscience Rita Levi-Montalcini, University of Turin, 10126 Turin, Italy; Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano (TO), ItalyDepartment of Neuroscience Rita Levi-Montalcini, University of Turin, 10126 Turin, Italy; Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano (TO), ItalyLaboratory of Translational Neuroscience, Ceinge Biotecnologie Avanzate “Franco Salvatore”, 80145 Naples, Italy; Department of Agricultural Sciences, University of Naples “Federico II”, 80055 Portici, ItalyCenter for Motor Neuron Biology and Disease, Columbia University, New York 10032, NY, USA; Department of Neurology, Columbia University, New York, 10032, NY, USA; Department of Pathology and Cell Biology, Columbia University, New York, 10032, NY, USALaboratory of Translational Neuroscience, Ceinge Biotecnologie Avanzate “Franco Salvatore”, 80145 Naples, Italy; European School of Molecular Medicine, University of Milan, 20122 Milan, Italy; Department of Environmental, Biological and Pharmaceutical Science and Technologies, University of Campania ''Luigi Vanvitelli'', 81100 Caserta, Italy; Corresponding author at: Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, Via A. Vivaldi, 43, 81100 Caserta, Italy.Spinal Muscular Atrophy (SMA) is a progressive neuromuscular disorder caused by homozygous loss of the survival motor neuron 1 (SMN1) gene, leading to reduced SMN protein expression. Increasing evidence implicates neurotransmission deficits in the pathophysiology of SMA. In particular, alterations in neuroactive amino acids involved in glutamatergic neurotransmission have recently been identified in both the cerebrospinal fluid (CSF) of SMApatients and the spinal cord of SMNΔ7 mouse models. L-arginine, a precursor of nitric oxide, plays a critical role in glutamatergic receptor signalling, influencing neurotransmitter release, synaptic plasticity, and neuroprotection. However, it remains unclear whether SMN deficiency affects L-arginine metabolism in SMA. To address this, we used high-performance liquid chromatography to investigate whether SMN deficiency alters L-arginine homeostasis in the central nervous system of SMNΔ7 mice and in the CSF of SMA patients with varying disease severity, both before and after treatment with the SMN-inducing therapy Nusinersen. Notably, we observed significantly reduced L-arginine levels in the brainstem and spinal cord of symptomatic SMA mice compared to age-matched wild-type littermates. Consistent with these findings, we revealed lower L-arginine levels in severe SMA1 patients compared to milder SMA2 and SMA3 patients and healthy controls, enhancing the translational strength of our findings. Importantly, Nusinersen-mediated SMN upregulation fully restored L-arginine homeostasis in the CSF of severe SMA1 patients. In conclusion, our results demonstrate a dysregulation of L-arginine in SMA and highlight a role for SMN-enhancing therapies in restoring neurochemical alterations observed in patients with this neurodegenerative disease.http://www.sciencedirect.com/science/article/pii/S0969996125002621Spinal muscular atrophyCereberal spinal fluidNusinersenL-arginineSMNΔ7 mice |
| spellingShingle | Amber Hassan Raffaella di Vito Anna Caretto Tommaso Nuzzo Adele D'Amico Chiara Panicucci Claudio Bruno Enrico Bertini Alessandro Vercelli Marina Boido Francesco Errico Livio Pellizzoni Alessandro Usiello Nusinersen corrects L-arginine deficiency in the cerebrospinal fluid of patients with severe spinal muscular atrophy Neurobiology of Disease Spinal muscular atrophy Cereberal spinal fluid Nusinersen L-arginine SMNΔ7 mice |
| title | Nusinersen corrects L-arginine deficiency in the cerebrospinal fluid of patients with severe spinal muscular atrophy |
| title_full | Nusinersen corrects L-arginine deficiency in the cerebrospinal fluid of patients with severe spinal muscular atrophy |
| title_fullStr | Nusinersen corrects L-arginine deficiency in the cerebrospinal fluid of patients with severe spinal muscular atrophy |
| title_full_unstemmed | Nusinersen corrects L-arginine deficiency in the cerebrospinal fluid of patients with severe spinal muscular atrophy |
| title_short | Nusinersen corrects L-arginine deficiency in the cerebrospinal fluid of patients with severe spinal muscular atrophy |
| title_sort | nusinersen corrects l arginine deficiency in the cerebrospinal fluid of patients with severe spinal muscular atrophy |
| topic | Spinal muscular atrophy Cereberal spinal fluid Nusinersen L-arginine SMNΔ7 mice |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125002621 |
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