Gene therapy for overexpressing Neuregulin 1 type I in skeletal muscles promotes functional improvement in the SOD1G93A ALS mice

Neurobiology of Disease

Neus Solanes¹  Rubèn López-Vales¹  Mireia Herrando-Grabulosa¹  Rosario Osta²  Xavier Navarro³  Sergi Verdés⁴  Assumpció Bosch⁴  Ana Cristina Calvo⁵  Guillem Mòdol-Caballero⁶  Belén García-Lareu⁶  Isaac Francos-Quijorna⁶ 

[1] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain;Department of Biochemistry and Molecular Biology, Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Spain;Laboratory of Genetics and Biochemistry (LAGENBIO), Faculty of Veterinary-IIS, University of Zaragoza, Zaragoza, Spain;Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain;Department of Biochemistry and Molecular Biology, Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Spain;Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autonoma de Barcelona, Bellaterra, Spain;

关键词: Neuregulin 1;    ErbB receptors;    Motoneuron;    Motor function;    Amyotrophic lateral sclerosis;    Spinal cord;   

DOI  :  

来源: DOAJ

【 摘 要 】

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motoneurons (MNs), with no effective treatment currently available. The molecular mechanisms that are involved in MN death are complex and not fully understood, with partial contributions of surrounding glial cells and skeletal muscle to the disease. Neuregulin 1 (NRG1) is a trophic factor highly expressed in MNs and neuromuscular junctions. Recent studies have suggested a crucial role of the isoform I (NRG1-I) in the collateral reinnervation process in skeletal muscle, and NRG1-III in the preservation of MNs in the spinal cord, opening a window for developing novel therapies for neuromuscular diseases like ALS. In this study, we overexpressed NRG1-I widely in the skeletal muscles of the SOD1G93A transgenic mouse. The results show that NRG1 gene therapy activated the survival pathways in muscle and spinal cord, increasing the number of surviving MNs and neuromuscular junctions and reducing the astroglial reactivity in the spinal cord of the treated SOD1G93A mice. Furthermore, NRG1-I overexpression preserved motor function and delayed the onset of clinical disease. In summary, our data indicates that NRG1 plays an important role on MN survival and muscle innervation in ALS, and that viral-mediated overexpression of NRG1 isoforms may be considered as a promising approach for ALS treatment.

【 授权许可】

Unknown