Spatial characterization of the lower motor neuron circuitry of a FUS-ALS mouse model


Pre-Clinical Research

Poster Number: M215


Diana Piol, PhD, VIB-KU Leuven Center for Brain and Disease Research, Sandrine Da Cruz, PhD, VIB-KU Leuven Center for Brain and Disease Research

Mutations in the protein fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease characterized by the death of motor neurons. This fatal disease is accompanied by axonal degeneration and neuromuscular junction denervation. The molecular mechanisms underlying the degeneration of the lower motor circuitry is not yet understood. For this reason, we employed spatial transcriptomics to unravel for the first time the in vivo transcriptome of spinal cord motor neurons, sciatic nerve motor axons and neuromuscular junctions in a FUS-ALS mouse model which recapitulates a late onset ALS-like phenotype. We discovered that multiple translation factors together with ribosomal proteins are dysregulated in a compartment-specific manner. Using multiplexed single-molecule RNA fluorescent in situ hybridization, super resolution microscopy and functional assays, the axon-specific alterations of components of the translation machinery were validated, further uncovering a strategy to boost local axonal translation in FUS-ALS. Our results reveal an unexplored pathway to increase local axonal translation in FUS-ALS motor neurons, which may represent an attractive therapeutic approach to restore motor function.