气候变化领域集成服务门户(CCPortal): Impairment of the neurotrophic signaling hub B-Raf contributes to motoneuron degeneration in spinal muscular atrophy

CCPortal

DOI	10.1073/pnas.2007785118
	Impairment of the neurotrophic signaling hub B-Raf contributes to motoneuron degeneration in spinal muscular atrophy
	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 A.K.; Richter M.F.; Jung K.; Corti S.; Di Schiavi E.; Claus P.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:18
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	14-3-3; Neurotrophic signaling; Raf; SMA; Spinal muscular atrophy
语种	英语
scopus关键词	B Raf kinase; mitogen activated protein kinase; protein kinase B; stratifin; B Raf kinase; Caenorhabditis elegans protein; lin-45 protein, C elegans; protein 14 3 3; Raf protein; SMN1 protein, human; survival motor neuron protein 1; animal experiment; animal model; animal tissue; Article; Caenorhabditis elegans; cell survival; controlled study; down regulation; fibroblast; motoneuron; mouse; nerve cell degeneration; nonhuman; priority journal; protein expression; protein protein interaction; protein structure; signal transduction; spinal muscular atrophy; animal; disease model; gene expression regulation; genetics; human; metabolism; motoneuron; nerve degeneration; pathology; signal transduction; spinal cord; spinal muscular atrophy; 14-3-3 Proteins; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Disease Models, Animal; Fibroblasts; Gene Expression Regulation; Humans; Mice; Motor Neurons; Muscular Atrophy, Spinal; Nerve Degeneration; Proto-Oncogene Proteins B-raf; raf Kinases; Signal Transduction; Spinal Cord; Survival of Motor Neuron 1 Protein
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251196
作者单位	Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, 30625, Germany; Center for Systems Neuroscience, Hannover, 30559, Germany; Institute of Biosciences and BioResources, National Research Council, Naples, 80131, Italy; Department of Biology, University of Naples Federico II, Naples, 80126, Italy; Neuroscience Section, Department of Pathophysiology and Transplantation, Dino Ferrari Centre, University of Milan, Milan, 20122, Italy; Institute of Human Genetics, Hannover Medical School, Hannover, 30625, Germany; Department of Neonatology, Children's and Youth Hospital Auf der Bult, Hannover, 30173, Germany; Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, 30559, Germany; Neurology Unit, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, Milan, 20122, Italy
推荐引用方式 GB/T 7714	Hensel N.,Cieri F.,Santonicola P.,et al. Impairment of the neurotrophic signaling hub B-Raf contributes to motoneuron degeneration in spinal muscular atrophy[J],2021,118(18).
APA	Hensel N..,Cieri F..,Santonicola P..,Tapken I..,Schüning T..,...&Claus P..(2021).Impairment of the neurotrophic signaling hub B-Raf contributes to motoneuron degeneration in spinal muscular atrophy.Proceedings of the National Academy of Sciences of the United States of America,118(18).
MLA	Hensel N.,et al."Impairment of the neurotrophic signaling hub B-Raf contributes to motoneuron degeneration in spinal muscular atrophy".Proceedings of the National Academy of Sciences of the United States of America 118.18(2021).