Impairment of the neurotrophic signaling hub B-Raf contributes to motoneuron degeneration in spinal muscular atrophy
| العنوان: | Impairment of the neurotrophic signaling hub B-Raf contributes to motoneuron degeneration in spinal muscular atrophy |
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| المؤلفون: | Manuela F. Richter, Stefania Corti, Pamela Santonicola, Michela Taiana, Silke Fischer, Tobias Schüning, Natascha Heidrich, Elisa Pagliari, Sabrina Kubinski, Elia Di Schiavi, Klaus Jung, Peter Claus, Antonia Joseph, Anke K. Bergmann, Federica Cieri, Hella Brinkmann, Ines Tapken, Niko Hensel |
| المصدر: | Proc Natl Acad Sci U S A Proceedings of the National Academy of Sciences of the United States of America (Online) (2021). doi:10.1073/pnas.2007785118 info:cnr-pdr/source/autori:Hensel N, Cieri F, Santonicola P, Tapken I, Schüning T, Taiana M, Pagliari E, Joseph A, Fischer S, Heidrich N, Brinkmann H, Kubinski S, Bergmann AK, Richter MF, Jung K, Corti S, Di Schiavi E, Claus P./titolo:Impairment of the neurotrophic signaling hub B-Raf contributes to motoneuron degeneration in spinal muscular atrophy/doi:10.1073%2Fpnas.2007785118/rivista:Proceedings of the National Academy of Sciences of the United States of America (Online)/anno:2021/pagina_da:/pagina_a:/intervallo_pagine:/volume |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Proto-Oncogene Proteins B-raf, MAPK/ERK pathway, SMN1, Biology, Muscular Atrophy, Spinal, Mice, medicine, Animals, Humans, SMA, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Protein kinase B, 14-3-3, spinal muscular atrophy, Motor Neurons, Multidisciplinary, Raf, Spinal muscular atrophy, Biological Sciences, Fibroblasts, medicine.disease, biology.organism_classification, Survival of Motor Neuron 1 Protein, neurotrophic signaling, Cell biology, Disease Models, Animal, 14-3-3 Proteins, Gene Expression Regulation, Spinal Cord, nervous system, Nerve Degeneration, biology.protein, raf Kinases, Signal transduction, Signal Transduction, Neurotrophin |
| الوصف: | Spinal muscular atrophy (SMA) is a motoneuron disease caused by deletions of the Survival of Motoneuron 1 gene (SMN1) and low SMN protein levels. SMN restoration is the concept behind a number of recently approved drugs which result in impressive yet limited effects. Since SMN has already been enhanced in treated patients, complementary SMN-independent approaches are needed. Previously, a number of altered signaling pathways which regulate motoneuron degeneration have been identified as candidate targets. However, signaling pathways form networks, and their connectivity is still unknown in SMA. Here, we used presymptomatic SMA mice to elucidate the network of altered signaling in SMA. The SMA network is structured in two clusters with AKT and 14-3-3 ζ/δ in their centers. Both clusters are connected by B-Raf as a major signaling hub. The direct interaction of B-Raf with 14-3-3 ζ/δ is important for an efficient neurotrophic activation of the MEK/ERK pathway and crucial for motoneuron survival. Further analyses in SMA mice revealed that both proteins were down-regulated in motoneurons and the spinal cord with B-Raf being reduced at presymptomatic stages. Primary fibroblasts and iPSC-derived motoneurons from SMA patients both showed the same pattern of down-regulation. This mechanism is conserved across species since a Caenorhabditis elegans SMA model showed less expression of the B-Raf homolog lin-45. Accordingly, motoneuron survival was rescued by a cell autonomous lin-45 expression in a C. elegans SMA model resulting in improved motor functions. This rescue was effective even after the onset of motoneuron degeneration and mediated by the MEK/ERK pathway. |
| تدمد: | 1091-6490 0027-8424 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4b651af1752779ced779f4a1559a729dTest https://doi.org/10.1073/pnas.2007785118Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....4b651af1752779ced779f4a1559a729d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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