27^th Euro-Global Neurologists Meeting

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder leading to the eventual death of motor neurons. Described cases of familial ALS have emphasized the significance of protein misfolding and aggregation of two functionally related proteins, FUS and TDP-43, implicated in RNA metabolism. Here in, using the in vivo model of FUS-mediated proteinopathy

(ΔFUS1-359 mice) we performed the comprehensive analysis encompassing the onset of the first clinical symptoms inclusions formations as well as changes in gene expression profile in motor neurons and surrounding microglia. The obtained data enable to conclude that FUS-mediated proteinopathy is virtually asymptomatic in terms of both the clinical symptoms and molecular aspects of neurodegeneration until it reaches the terminal stage of disease progression (120 days age). From this time point the pathological process develops very rapidly resulting in massive FUS-positive inclusions formation accompanying the transcriptional burst in the spinal cord cells. Specifically, it manifests in activation of pro-inflammatory phenotype of microglial cells and malfunction of acetylcholine synapse transmission in motor neurons. Overall, we assume that a highly reproducible course of the pathological process, as well as described accompanying features, make ΔFUS1-359 mice a convenient model for testing potential therapeutics against proteinopathy-induced decay of motor neurons.