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

• DOI: 10.1038/s42003-021-02538-8
• Publication Date: 2021-09-01T10:04:51Z
• Authors: Maria Giovanna Ga...; Nicol Birsa; Maria Rosito; Federico Salaris; Michela Mochi; Valeria de Turris; Remya R. Nair; Thomas J. Cunningham; Elizabeth M. C. F...; Mariangela Morlando; Pietro Fratta; Alessandro Rosa
• Keywords: 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)

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.