| Autor: |
Gonzalez D; Centro de Envejecimiento y Regeneración, CARE Chile UC, Santiago, Chile.; Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile., Rebolledo DL; Centro de Envejecimiento y Regeneración, CARE Chile UC, Santiago, Chile.; Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile., Correa LM; Centro de Envejecimiento y Regeneración, CARE Chile UC, Santiago, Chile.; Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile., Court FA; Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile., Cerpa W; Centro de Envejecimiento y Regeneración, CARE Chile UC, Santiago, Chile.; Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile., Lipson KE; FibroGen, Inc., Research Department, San Francisco, CA, USA., van Zundert B; Centro de Envejecimiento y Regeneración, CARE Chile UC, Santiago, Chile.; Centro de Investigaciones Biomédicas, Facultad de Ciencias Biológicas y Facultad de Medicina, Universidad Andres Bello, Santiago, Chile., Brandan E; Centro de Envejecimiento y Regeneración, CARE Chile UC, Santiago, Chile.; Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile. |
| Abstrakt: |
Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset progressive neurodegenerative disease characterized by upper and lower motoneuron degeneration. A total of 20% of familial ALS (fALS) cases are explained by mutations in the superoxide dismutase 1 (SOD1) enzyme. Although more than 20 years have passed since the generation of the first ALS mouse model, the precise molecular mechanisms of ALS pathogenesis remain unknown. CTGF/CCN2 is a matricellular protein with associated fibrotic activity that is up-regulated in several chronic diseases. The inhibition of CTGF/CCN2 with the monoclonal neutralizing antibody FG-3019 reduces fibrosis in several chronic disorders including the mdx mice, a murine model for Duchenne muscular dystrophy (DMD). In this work, we show that there are increased levels of CTGF/CCN2 in skeletal muscle and spinal cord of hSOD1G93A mice. In this scenario, we show evidence that FG-3019 not only reduces fibrosis in skeletal muscle of hSOD1G93A mice, but also improves muscle and locomotor performance. We demonstrate that treatment with FG-3019 reduces muscle atrophy in hSOD1G93A mice. We also found improvement of neuromuscular junction (NMJ) innervation together with a reduction in myelin degeneration in the sciatic nerve, suggesting that alterations in nerve-muscle communication are partially improved in FG-3019-treated hSOD1G93A mice. Moreover, we also found that CTGF/CCN2 is expressed in astrocytes and neurons, predominantly in dorsal areas of spinal cord from symptomatic hSOD1G93A mice. Together, these results reveal that CTGF/CCN2 might be a novel therapeutic target to ameliorate symptoms and improve the quality of life of ALS patients. |
