FUSDelta14 mutation impairs normal brain development and causes systemic metabolic alterations

Abstract

FUS (Fused in sarcoma) is a ubiquitously expressed RNA binding protein, which is mislocalized and aggregated in some forms of frontotemporal dementia (FTD), whilst mutations in FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS), as in the case with the FUSDelta14 mutation. Most studies have focused on the role of FUS in motor neuron degeneration, although it is unknown whether FUS mutations affect other cell and tissue types, and the neurodevelopmental impact of FUS mutation on the nervous system is unclear. Here we studied pleiotropic phenotypes in a physiological knock-in mouse model carrying a partially humanised FUSDelta14 mutation in homozygosity. We performed RNA sequencing of six different tissues (frontal cortex, spinal cord, tibialis anterior muscle, white and brown adipose tissue and liver) and found that the genes and pathways affected were generally tissue-specific and showed few commonalities. Phenotypic assessment of homozygous FUSDelta14 mice revealed systemic metabolic alterations related to the pathway changes identified. Homozygous FUSDelta14 brains displayed significant morphological alterations including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with fatal seizures in early adult life. Altogether, our data supports a wide-ranging role for FUS, and suggests that the disease aetiology of FUS mutation can include developmental and pleiotropic phenotypes.