Impairment of the neurotrophic signaling hub B-Raf contributes to motoneuron degeneration in spinal muscular atrophy

Niko Hensel, Federica Cieri, Pamela Santonicola, Ines Tapken, Tobias Schüning, Michela Taiana, Elisa Pagliari, Antonia Joseph, Silke Fischer, Natascha Heidrich, Hella Brinkmann, Sabrina Kubinski, Anke K. Bergmann, Manuela F. Richter, Klaus Jung, Stefania Corti, Elia Di Schiavi, Peter Claus

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number2007785118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number18
DOIs
Publication statusPublished - May 4 2021

Keywords

  • 14-3-3
  • Neurotrophic signaling
  • Raf
  • SMA
  • Spinal muscular atrophy

ASJC Scopus subject areas

  • General

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