Early mitochondrial gene dysregulation precedes motor neuron degeneration in genomically humanised FUS mutant mice

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, with mutations in the Fused in Sarcoma (FUS) gene accounting for some of the most aggressive forms of the disease. Although FUS mutations are rare, accounting for only around 5% of all familial ALS cases, they are an important paradigm for study because FUS is an RNA binding protein and disruption to RNA metabolism is prominent across ALS subtypes. Here we present two novel, genomically humanised gene-targeted FUS mouse models expressing ALS patient mutations P525L or Q519Ifs. These humanised models express only human FUS protein under physiological control of the endogenous mouse promoter. Humanised knock-in hFUSP525L mice developed a mid-life onset reduction in motor performance with neuromuscular denervation, motor neuron loss, and unilateral limb muscle weakness. Pre-symptomatic transcriptomic changes suggested metabolic impairments as an early phenotype in skeletal muscle. We also directly compared phenotypes between hFUSP525L and hFUSQ519Ifs expressing mice. hFUSQ519Ifs expressing mice were more severely affected, including a pronounced developmental phenotype which varied in severity on different genetic backgrounds. The phenotypes of these new FUS-ALS models highlight the potential of fully humanised knock-in mice to aid in unravelling early disease mechanisms, and ultimately to assist in the development of therapies targeted towards the human FUS gene and protein in ALS.