Catecholaminergic dysfunction drives postural and locomotor deficits in a mouse model of spinal muscular atrophy
Summary: Development and maintenance of posture is essential behavior for overground mammalian locomotion. Dopamine and noradrenaline strongly influence locomotion, and their dysregulation initiates the development of motor impairments linked to neurodegenerative disease. However, the precise cellul...
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| Language: | English |
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Elsevier
2025-01-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724014980 |
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| author | John G. Pagiazitis Nicolas Delestrée Leonie Sowoidnich Nandhini Sivakumar Christian M. Simon Athanasios Chatzisotiriou Maria Albani George Z. Mentis |
| author_facet | John G. Pagiazitis Nicolas Delestrée Leonie Sowoidnich Nandhini Sivakumar Christian M. Simon Athanasios Chatzisotiriou Maria Albani George Z. Mentis |
| author_sort | John G. Pagiazitis |
| collection | DOAJ |
| description | Summary: Development and maintenance of posture is essential behavior for overground mammalian locomotion. Dopamine and noradrenaline strongly influence locomotion, and their dysregulation initiates the development of motor impairments linked to neurodegenerative disease. However, the precise cellular and circuit mechanisms are not well defined. Here, we investigated the role of catecholaminergic neuromodulation in a mouse model of spinal muscular atrophy (SMA). SMA is characterized by severe motor dysfunction and postural deficits. We identify progressive loss of catecholaminergic synapses from spinal neurons that occur via non-cell autonomous mechanisms. Importantly, the selective restoration of survival motor neuron (SMN) in either catecholaminergic or serotonergic neurons is sufficient to correct impairments in locomotion. However, only combined SMN restoration in both catecholaminergic and serotonergic neurons or pharmacological treatment with l-dopa improve the severe postural deficits. These findings uncover the synaptic and cellular mechanisms responsible for the postural and motor symptoms in SMA and identify catecholaminergic neuromodulation as a potential therapeutic target. |
| format | Article |
| id | doaj-art-4d6e971637924509ad5d49d6bb9a2a4e |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-4d6e971637924509ad5d49d6bb9a2a4e2025-01-04T04:56:16ZengElsevierCell Reports2211-12472025-01-01441115147Catecholaminergic dysfunction drives postural and locomotor deficits in a mouse model of spinal muscular atrophyJohn G. Pagiazitis0Nicolas Delestrée1Leonie Sowoidnich2Nandhini Sivakumar3Christian M. Simon4Athanasios Chatzisotiriou5Maria Albani6George Z. Mentis7Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USA; Department of Physiology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 541 24, GreeceCenter for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USACenter for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USA; Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig, GermanyCenter for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USACarl-Ludwig-Institute for Physiology, Leipzig University, Leipzig, GermanyDepartment of Physiology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 541 24, GreeceDepartment of Physiology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 541 24, GreeceCenter for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Corresponding authorSummary: Development and maintenance of posture is essential behavior for overground mammalian locomotion. Dopamine and noradrenaline strongly influence locomotion, and their dysregulation initiates the development of motor impairments linked to neurodegenerative disease. However, the precise cellular and circuit mechanisms are not well defined. Here, we investigated the role of catecholaminergic neuromodulation in a mouse model of spinal muscular atrophy (SMA). SMA is characterized by severe motor dysfunction and postural deficits. We identify progressive loss of catecholaminergic synapses from spinal neurons that occur via non-cell autonomous mechanisms. Importantly, the selective restoration of survival motor neuron (SMN) in either catecholaminergic or serotonergic neurons is sufficient to correct impairments in locomotion. However, only combined SMN restoration in both catecholaminergic and serotonergic neurons or pharmacological treatment with l-dopa improve the severe postural deficits. These findings uncover the synaptic and cellular mechanisms responsible for the postural and motor symptoms in SMA and identify catecholaminergic neuromodulation as a potential therapeutic target.http://www.sciencedirect.com/science/article/pii/S2211124724014980CP: Neuroscience |
| spellingShingle | John G. Pagiazitis Nicolas Delestrée Leonie Sowoidnich Nandhini Sivakumar Christian M. Simon Athanasios Chatzisotiriou Maria Albani George Z. Mentis Catecholaminergic dysfunction drives postural and locomotor deficits in a mouse model of spinal muscular atrophy Cell Reports CP: Neuroscience |
| title | Catecholaminergic dysfunction drives postural and locomotor deficits in a mouse model of spinal muscular atrophy |
| title_full | Catecholaminergic dysfunction drives postural and locomotor deficits in a mouse model of spinal muscular atrophy |
| title_fullStr | Catecholaminergic dysfunction drives postural and locomotor deficits in a mouse model of spinal muscular atrophy |
| title_full_unstemmed | Catecholaminergic dysfunction drives postural and locomotor deficits in a mouse model of spinal muscular atrophy |
| title_short | Catecholaminergic dysfunction drives postural and locomotor deficits in a mouse model of spinal muscular atrophy |
| title_sort | catecholaminergic dysfunction drives postural and locomotor deficits in a mouse model of spinal muscular atrophy |
| topic | CP: Neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724014980 |
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