Suppression of the necroptotic cell death pathways improves survival in Smn2B/− mice
Spinal muscular atrophy (SMA) is a monogenic neuromuscular disease caused by low levels of the Survival Motor Neuron (SMN) protein. Motor neuron degeneration is the central hallmark of the disease. However, the SMN protein is ubiquitously expressed and depletion of the protein in peripheral tissues...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2022.972029/full |
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| author | Lucia Chehade Lucia Chehade Lucia Chehade Marc-Olivier Deguise Marc-Olivier Deguise Marc-Olivier Deguise Marc-Olivier Deguise Yves De Repentigny Rebecca Yaworski Ariane Beauvais Sabrina Gagnon Niko Hensel Rashmi Kothary Rashmi Kothary Rashmi Kothary Rashmi Kothary Rashmi Kothary |
| author_facet | Lucia Chehade Lucia Chehade Lucia Chehade Marc-Olivier Deguise Marc-Olivier Deguise Marc-Olivier Deguise Marc-Olivier Deguise Yves De Repentigny Rebecca Yaworski Ariane Beauvais Sabrina Gagnon Niko Hensel Rashmi Kothary Rashmi Kothary Rashmi Kothary Rashmi Kothary Rashmi Kothary |
| author_sort | Lucia Chehade |
| collection | DOAJ |
| description | Spinal muscular atrophy (SMA) is a monogenic neuromuscular disease caused by low levels of the Survival Motor Neuron (SMN) protein. Motor neuron degeneration is the central hallmark of the disease. However, the SMN protein is ubiquitously expressed and depletion of the protein in peripheral tissues results in intrinsic disease manifestations, including muscle defects, independent of neurodegeneration. The approved SMN-restoring therapies have led to remarkable clinical improvements in SMA patients. Yet, the presence of a significant number of non-responders stresses the need for complementary therapeutic strategies targeting processes which do not rely solely on restoring SMN. Dysregulated cell death pathways are candidates for SMN-independent pathomechanisms in SMA. Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 have been widely recognized as critical therapeutic targets of necroptosis, an important form of programmed cell death. In addition, Caspase-1 plays a fundamental role in inflammation and cell death. In this study, we evaluate the role of necroptosis, particularly RIPK3 and Caspase-1, in the Smn2B/− mouse model of SMA. We have generated a triple mutant (TKO), the Smn2B/−; Ripk3−/−; Casp1−/− mouse. TKO mice displayed a robust increase in survival and improved motor function compared to Smn2B/− mice. While there was no protection against motor neuron loss or neuromuscular junction pathology, larger muscle fibers were observed in TKO mice compared to Smn2B/− mice. Our study shows that necroptosis modulates survival, motor behavior and muscle fiber size independent of SMN levels and independent of neurodegeneration. Thus, small-molecule inhibitors of necroptosis as a combinatorial approach together with SMN-restoring drugs could be a future strategy for the treatment of SMA. |
| first_indexed | 2024-12-11T18:53:10Z |
| format | Article |
| id | doaj.art-7012f123c6254c638026160eccd82345 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-11T18:53:10Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-7012f123c6254c638026160eccd823452022-12-22T00:54:14ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022022-08-011610.3389/fncel.2022.972029972029Suppression of the necroptotic cell death pathways improves survival in Smn2B/− miceLucia Chehade0Lucia Chehade1Lucia Chehade2Marc-Olivier Deguise3Marc-Olivier Deguise4Marc-Olivier Deguise5Marc-Olivier Deguise6Yves De Repentigny7Rebecca Yaworski8Ariane Beauvais9Sabrina Gagnon10Niko Hensel11Rashmi Kothary12Rashmi Kothary13Rashmi Kothary14Rashmi Kothary15Rashmi Kothary16Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, CanadaDepartment of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, CanadaCenter for Neuromuscular Disease, University of Ottawa, Ottawa, ON, CanadaRegenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, CanadaDepartment of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, CanadaCenter for Neuromuscular Disease, University of Ottawa, Ottawa, ON, CanadaDepartment of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, CanadaRegenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, CanadaRegenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, CanadaRegenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, CanadaRegenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, CanadaRegenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, CanadaRegenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, CanadaDepartment of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, CanadaCenter for Neuromuscular Disease, University of Ottawa, Ottawa, ON, CanadaDepartment of Medicine, University of Ottawa, Ottawa, ON, CanadaDepartment of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, CanadaSpinal muscular atrophy (SMA) is a monogenic neuromuscular disease caused by low levels of the Survival Motor Neuron (SMN) protein. Motor neuron degeneration is the central hallmark of the disease. However, the SMN protein is ubiquitously expressed and depletion of the protein in peripheral tissues results in intrinsic disease manifestations, including muscle defects, independent of neurodegeneration. The approved SMN-restoring therapies have led to remarkable clinical improvements in SMA patients. Yet, the presence of a significant number of non-responders stresses the need for complementary therapeutic strategies targeting processes which do not rely solely on restoring SMN. Dysregulated cell death pathways are candidates for SMN-independent pathomechanisms in SMA. Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 have been widely recognized as critical therapeutic targets of necroptosis, an important form of programmed cell death. In addition, Caspase-1 plays a fundamental role in inflammation and cell death. In this study, we evaluate the role of necroptosis, particularly RIPK3 and Caspase-1, in the Smn2B/− mouse model of SMA. We have generated a triple mutant (TKO), the Smn2B/−; Ripk3−/−; Casp1−/− mouse. TKO mice displayed a robust increase in survival and improved motor function compared to Smn2B/− mice. While there was no protection against motor neuron loss or neuromuscular junction pathology, larger muscle fibers were observed in TKO mice compared to Smn2B/− mice. Our study shows that necroptosis modulates survival, motor behavior and muscle fiber size independent of SMN levels and independent of neurodegeneration. Thus, small-molecule inhibitors of necroptosis as a combinatorial approach together with SMN-restoring drugs could be a future strategy for the treatment of SMA.https://www.frontiersin.org/articles/10.3389/fncel.2022.972029/fullneuroinflammationnecroptosismotor neuron disease (MND)multi-system diseasemouse genetic models |
| spellingShingle | Lucia Chehade Lucia Chehade Lucia Chehade Marc-Olivier Deguise Marc-Olivier Deguise Marc-Olivier Deguise Marc-Olivier Deguise Yves De Repentigny Rebecca Yaworski Ariane Beauvais Sabrina Gagnon Niko Hensel Rashmi Kothary Rashmi Kothary Rashmi Kothary Rashmi Kothary Rashmi Kothary Suppression of the necroptotic cell death pathways improves survival in Smn2B/− mice Frontiers in Cellular Neuroscience neuroinflammation necroptosis motor neuron disease (MND) multi-system disease mouse genetic models |
| title | Suppression of the necroptotic cell death pathways improves survival in Smn2B/− mice |
| title_full | Suppression of the necroptotic cell death pathways improves survival in Smn2B/− mice |
| title_fullStr | Suppression of the necroptotic cell death pathways improves survival in Smn2B/− mice |
| title_full_unstemmed | Suppression of the necroptotic cell death pathways improves survival in Smn2B/− mice |
| title_short | Suppression of the necroptotic cell death pathways improves survival in Smn2B/− mice |
| title_sort | suppression of the necroptotic cell death pathways improves survival in smn2b mice |
| topic | neuroinflammation necroptosis motor neuron disease (MND) multi-system disease mouse genetic models |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2022.972029/full |
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