In a (35) thirty-five-minute lecture delivered by Dr. Luc Dupuis elucidates on the implications of FUS mutations in amyotrophic lateral sclerosis (ALS), emphasizing the autosomal dominant nature and rapid progression, particularly in juvenile cases. The discussion focuses on the clustering of mutations in the C-terminal NLS part of FUS, leading to impaired nuclear import. The Dormann & Haass working model is explored, with rigorous testing through homologous recombination, gene expression studies, and knockout mice experiments. Dr. Dupuis investigates the toxic effects of Fus mutations in motor neurons, revealing detrimental impacts on both motor phenotype and muscle function in Fus knock-in mice. Beyond ALS, the lecture explores the potential involvement of FUS in frontotemporal dementia (FTD), highlighting FUS inclusions in FTD and exploring transcriptional effects in the CNS. The presentation extends to systems biology, identifying co-regulated genes in Fus∆NLS/+ mice cortex, with a focus on mRNA processing and synaptic genes. Dr. Dupuis demonstrates how FUS mislocalization leads to cortical hyperexcitability and abnormal behavior, linking synaptic physiology to altered activity and social defects. The lecture concludes by addressing outstanding questions regarding therapeutic targeting of FUS mutations, exploring FUS autoregulation and innovative approaches like hijacking FUS autoregulation to generate genotypes of interest and test their effects on behavior and physiology.For further details, Watch a video