Dynamics of gene expression changes in the spinal cord during FUS-mediated proteinopathy

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder leading to the eventual death of motor neurons. Described cases of familial ALS have emerged the significance of protein misfolding and aggregation of two functionally related proteins, FUS and TDP-43, implicated in RNA metabolism. Herein, using the in vivo model of FUS-mediated proteinopathy (?FUS1-359 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 show that FUS-mediated proteinopathy is predominantly asymptomatic in terms of both the clinical symptoms and molecular aspects of neurodegeneration until it reaches the terminal stage of disease progression (120 days from birth). From this time point the pathological process develops very rapidly resulting in massive FUS-positive inclusions formation which is accompanying by 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. We conclude that a stable course of the pathological process, as well as described accompanying features, make ?FUS1-359 mice a convenient model for testing potential therapeutics against proteinopathy-induced decay of motor neurons. Overall design: RNA-sequencing of transgenic and non-transgenic mice cervical region of spinal cord