Gene Therapy Overexpressing Neuregulin 1 Type I in Combination With Neuregulin 1 Type III Promotes Functional Improvement in the SOD1G93A ALS Mice
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the neuromuscular system for which currently there is no effective therapy. Motoneuron (MN) degeneration involves several complex mechanisms, including surrounding glial cells and skeletal muscle contributions. Neureg...
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| Format: | Article |
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Frontiers Media S.A.
2021-09-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2021.693309/full |
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| author | Guillem Mòdol-Caballero Guillem Mòdol-Caballero Mireia Herrando-Grabulosa Mireia Herrando-Grabulosa Sergi Verdés Sergi Verdés Belén García-Lareu Belén García-Lareu Neus Hernández Neus Hernández Isaac Francos-Quijorna Isaac Francos-Quijorna Rubén López-Vales Rubén López-Vales Assumpció Bosch Assumpció Bosch Assumpció Bosch Xavier Navarro Xavier Navarro |
| author_facet | Guillem Mòdol-Caballero Guillem Mòdol-Caballero Mireia Herrando-Grabulosa Mireia Herrando-Grabulosa Sergi Verdés Sergi Verdés Belén García-Lareu Belén García-Lareu Neus Hernández Neus Hernández Isaac Francos-Quijorna Isaac Francos-Quijorna Rubén López-Vales Rubén López-Vales Assumpció Bosch Assumpció Bosch Assumpció Bosch Xavier Navarro Xavier Navarro |
| author_sort | Guillem Mòdol-Caballero |
| collection | DOAJ |
| description | Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the neuromuscular system for which currently there is no effective therapy. Motoneuron (MN) degeneration involves several complex mechanisms, including surrounding glial cells and skeletal muscle contributions. Neuregulin 1 (NRG1) is a trophic factor present particularly in MNs and neuromuscular junctions. Our previous studies revealed that gene therapy overexpressing the isoform I (NRG1-I) in skeletal muscles as well as overexpressing the isoform III (NRG1-III) directly in the central nervous system are both effective in preserving MNs in the spinal cord of ALS mice, opening novel therapeutic approaches. In this study, we combined administration of both viral vectors overexpressing NRG1-I in skeletal muscles and NRG1-III in spinal cord of the SOD1G93A mice in order to obtain a synergistic effect. The results showed that the combinatorial gene therapy increased preservation of MNs and of innervated neuromuscular junctions and reduced glial reactivity in the spinal cord of the treated SOD1G93A mice. Moreover, NRG1 isoforms overexpression improved motor function of hindlimb muscles and delayed the onset of clinical disease. However, this combinatory gene therapy did not produce a synergic effect compared with single therapies, suggesting an overlap between NRG1-I and NRG1-III activated pathways and their beneficial effects. |
| first_indexed | 2024-12-17T00:00:09Z |
| format | Article |
| id | doaj.art-de3aa861366a46a9a56f3e37e6182c97 |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-12-17T00:00:09Z |
| publishDate | 2021-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-de3aa861366a46a9a56f3e37e6182c972022-12-21T22:11:06ZengFrontiers Media S.A.Frontiers in Neurology1664-22952021-09-011210.3389/fneur.2021.693309693309Gene Therapy Overexpressing Neuregulin 1 Type I in Combination With Neuregulin 1 Type III Promotes Functional Improvement in the SOD1G93A ALS MiceGuillem Mòdol-Caballero0Guillem Mòdol-Caballero1Mireia Herrando-Grabulosa2Mireia Herrando-Grabulosa3Sergi Verdés4Sergi Verdés5Belén García-Lareu6Belén García-Lareu7Neus Hernández8Neus Hernández9Isaac Francos-Quijorna10Isaac Francos-Quijorna11Rubén López-Vales12Rubén López-Vales13Assumpció Bosch14Assumpció Bosch15Assumpció Bosch16Xavier Navarro17Xavier Navarro18Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autonoma de Barcelona, Barcelona, SpainCentro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, SpainDepartment of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autonoma de Barcelona, Barcelona, SpainCentro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, SpainDepartment of Biochemistry and Molecular Biology, Institute of Neurosciences, Universitat Autònoma De Barcelona, Barcelona, SpainUnitat Mixta UAB-VHIR, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, SpainCentro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, SpainDepartment of Biochemistry and Molecular Biology, Institute of Neurosciences, Universitat Autònoma De Barcelona, Barcelona, SpainDepartment of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autonoma de Barcelona, Barcelona, SpainCentro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, SpainDepartment of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autonoma de Barcelona, Barcelona, SpainCentro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, SpainDepartment of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autonoma de Barcelona, Barcelona, SpainCentro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, SpainCentro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, SpainDepartment of Biochemistry and Molecular Biology, Institute of Neurosciences, Universitat Autònoma De Barcelona, Barcelona, SpainUnitat Mixta UAB-VHIR, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, SpainDepartment of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autonoma de Barcelona, Barcelona, SpainCentro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, SpainAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the neuromuscular system for which currently there is no effective therapy. Motoneuron (MN) degeneration involves several complex mechanisms, including surrounding glial cells and skeletal muscle contributions. Neuregulin 1 (NRG1) is a trophic factor present particularly in MNs and neuromuscular junctions. Our previous studies revealed that gene therapy overexpressing the isoform I (NRG1-I) in skeletal muscles as well as overexpressing the isoform III (NRG1-III) directly in the central nervous system are both effective in preserving MNs in the spinal cord of ALS mice, opening novel therapeutic approaches. In this study, we combined administration of both viral vectors overexpressing NRG1-I in skeletal muscles and NRG1-III in spinal cord of the SOD1G93A mice in order to obtain a synergistic effect. The results showed that the combinatorial gene therapy increased preservation of MNs and of innervated neuromuscular junctions and reduced glial reactivity in the spinal cord of the treated SOD1G93A mice. Moreover, NRG1 isoforms overexpression improved motor function of hindlimb muscles and delayed the onset of clinical disease. However, this combinatory gene therapy did not produce a synergic effect compared with single therapies, suggesting an overlap between NRG1-I and NRG1-III activated pathways and their beneficial effects.https://www.frontiersin.org/articles/10.3389/fneur.2021.693309/fullamyotrophic lateral sclerosisneuregulin 1ErbB receptorsmotoneuronneuromuscular junctionspinal cord |
| spellingShingle | Guillem Mòdol-Caballero Guillem Mòdol-Caballero Mireia Herrando-Grabulosa Mireia Herrando-Grabulosa Sergi Verdés Sergi Verdés Belén García-Lareu Belén García-Lareu Neus Hernández Neus Hernández Isaac Francos-Quijorna Isaac Francos-Quijorna Rubén López-Vales Rubén López-Vales Assumpció Bosch Assumpció Bosch Assumpció Bosch Xavier Navarro Xavier Navarro Gene Therapy Overexpressing Neuregulin 1 Type I in Combination With Neuregulin 1 Type III Promotes Functional Improvement in the SOD1G93A ALS Mice Frontiers in Neurology amyotrophic lateral sclerosis neuregulin 1 ErbB receptors motoneuron neuromuscular junction spinal cord |
| title | Gene Therapy Overexpressing Neuregulin 1 Type I in Combination With Neuregulin 1 Type III Promotes Functional Improvement in the SOD1G93A ALS Mice |
| title_full | Gene Therapy Overexpressing Neuregulin 1 Type I in Combination With Neuregulin 1 Type III Promotes Functional Improvement in the SOD1G93A ALS Mice |
| title_fullStr | Gene Therapy Overexpressing Neuregulin 1 Type I in Combination With Neuregulin 1 Type III Promotes Functional Improvement in the SOD1G93A ALS Mice |
| title_full_unstemmed | Gene Therapy Overexpressing Neuregulin 1 Type I in Combination With Neuregulin 1 Type III Promotes Functional Improvement in the SOD1G93A ALS Mice |
| title_short | Gene Therapy Overexpressing Neuregulin 1 Type I in Combination With Neuregulin 1 Type III Promotes Functional Improvement in the SOD1G93A ALS Mice |
| title_sort | gene therapy overexpressing neuregulin 1 type i in combination with neuregulin 1 type iii promotes functional improvement in the sod1g93a als mice |
| topic | amyotrophic lateral sclerosis neuregulin 1 ErbB receptors motoneuron neuromuscular junction spinal cord |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2021.693309/full |
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