Role of FUS in post synaptic neuromuscular junction differentiation

author: Gina Picchiarelli, INSERM
published: July 21, 2017,   recorded: May 2017,   views: 1060


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During ALS disease progression, the neuromuscular junction (NMJ), that is the specialized synapse between the motor neuron and the muscle fiber, is the first structure to be affected. Indeed, the NMJ is dismantled before degeneration of motor neuron cell body. Results from our laboratory also implicate muscle metabolic defects in the neurodegeneration observed in ALS patients and models. A subset of ALS cases is caused by dominantly inherited mutations in the gene encoding FUS, a RNA-binding protein involved in multiple steps of RNA metabolism. ALS-linked FUS mutations cause typical ALS, with young onset and rapid disease progression. Most of the known FUS mutations alter the import of FUS in the nucleus, and the mutations leading to the most severe clinical pictures are truncating mutations deleting the C-terminal nuclear localization signal (NLS). Our laboratory previously developed a conditional Fus Knock-In model of ALS (Scekic-Zahirovic et al., EMBO J, 2016; Scekic- Zahirovic, Acta Neuropathol, 2017). These mice display a constitutive deletion of NLS that can be rescued to the wild type situation upon CRE-mediated recombination. We observed that the complete cytoplasmic mislocalization of FUS in homozygous Knock-In mice leads to perinatal death, accompanied by motor neuron degeneration. Interestingly, rescuing FUS localization in motor neurons rescued motor neuron degeneration, yet perinatal death was not rescued. Our working hypothesis is that Fus mutation is primarily causing defects in NMJ structure and differentiation. Indeed in a cell model, FUS is both necessary and sufficient to drive expression of acetylcholine receptor genes of the NMJ and in an animal model, complete Fus mislocalization showed ultrastructural presynaptic defects at the NMJ. Besides presynaptic defects, muscles of these mice showed abnormal post-synaptic acetylcholine receptor clusters, and this was associated with defects in expression of a number of NMJ-related genes in muscles. Furthermore, adult heterozygous Fus knock-in mice, showing partial cytoplasmic mislocalization of FUS, display smaller endplates. So, proper FUS function is required for the normal neuromuscular junction differentiation. The understanding of the role of FUS in NMJ structure and function could be instrumental in designing therapeutic strategies for FUS-ALS.

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