期刊
NEUROBIOLOGY OF DISEASE
卷 137, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2020.104793
关键词
Neuregulin 1; ErbB receptors; Motoneuron; Motor function; Amyotrophic lateral sclerosis; Spinal cord; Neuromuscular junction
资金
- Fundacio La Marato-TV3 [TV3201428-10]
- AFM-Telethon [20289]
- CIBERNED [201501]
- TERCEL funds [RD16/0011/0014]
- Instituto de Salud Carlos III of Spain [PS09720]
- European Union funds (ERDF/ESF, Investing in your future)
- Generalitat de Catalunya [2019 FI-B 00120]
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.
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