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

NEUROBIOLOGY OF DISEASE

卷:137

Article

Modol-Caballero, Guillem^1,2  Herrando-Grabulosa, Mireia^1,2  Garcia-Lareu, Bela^2,3  Solanes, Neus^1,2  Verdes, Sergi³  Osta, Rosario^2,4  Francos-Quijorna, Isaac^1,2,6  Lopez-Vales, Ruben^1,2  Cristina Calvo, Ana^2,4  Bosch, Assumpcio^2,3,5  Navarro, Xavier^1,2 

[1] Univ Autonoma Barcelona, Inst Neurosci, Dept Cell Biol Physiol & Immunol, Bellaterra, Spain

[2] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Bellaterra, Spain

[3] Univ Autonoma Barcelona, Inst Neurosci, Dept Biochem & Mol Biol, Bellaterra, Spain

[4] Univ Zaragoza, Fac Vet IIS, Lab Genet & Biochem LAGENBIO, Zaragoza, Spain

[5] Vall dHebron Res Inst VHIR, Barcelona, Spain

[6] Kings Coll London, Inst Psychiat Psychol & Neurosci IoPPN, Regenerat Grp, Wolfson Ctr Age Related Dis, London, England

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

DOI  :  10.1016/j.nbd.2020.104793

来源: Elsevier

【 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 SOD1(G93A) 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 as-troglial reactivity in the spinal cord of the treated SOD1(G93A) 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.