ALS-related FUS mutations alter axon growth in motoneurons and affect HuD/ELAVL4 and FMRP activity

RNA metabolism Motor Neurons 0301 basic medicine Motor neuron QH301-705.5 ELAV-Like Protein 4 Amyotrophic lateral sclerosis FUS; iPSC; motoneuron; axon; GAP43; NRN1; HuD; FMR1 Article Axons Cell Line Induced pluripotent stem cells Fragile X Mental Retardation Protein Mice 03 medical and health sciences Mechanisms of disease Mutation Animals Humans RNA-Binding Protein FUS Biology (General)
DOI: 10.1038/s42003-021-02538-8 Publication Date: 2021-09-01T10:04:51Z
ABSTRACT
Abstract Mutations in the RNA-binding protein (RBP) FUS have been genetically associated with motoneuron disease amyotrophic lateral sclerosis (ALS). Using both human induced pluripotent stem cells and mouse models, we found that FUS-ALS causative mutations affect activity of two relevant RBPs important roles neuronal RNA metabolism: HuD/ELAVL4 FMRP. Mechanistically, mutant leads to upregulation HuD levels through competition FMRP for mRNA 3’UTR binding. In turn, increased overly stabilize transcript its targets, NRN1 GAP43. As a consequence, motoneurons show axon branching growth upon injury, which could be rescued by dampening levels. Since similar phenotypes previously described SOD1 TDP-43 axonal might represent broad early events pathogenesis ALS.
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