Activity-dependent FUS dysregulation disrupts synaptic homeostasis

Abstract

Both overexpression of wild-type fused in sarcoma (FUS) protein and missense mutations can be pathogenic in a group of related neurodegenerative disorders that includes amyotrophic lateral sclerosis and frontotemporal lobar degeneration. It is unclear how FUS overexpression and missense mutations cause disease in human patients. In this work, we generated novel transgenic mouse models expressing low levels of wild-type and mutant human FUS, both of which recapitulate aspects of the human diseases. We found a profound difference in the underlying mechanisms by which missense mutation and wild-type overexpression cause disease. Overexpression of wild-type FUS protein alters its nuclear function at the level of gene expression. In contrast, missense mutation disrupts activity-dependent synaptic homeostasis to gain a toxic function at dendritic spines. The RNA-binding protein fused-in-sarcoma (FUS) has been associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two neurodegenerative disorders that share similar clinical and pathological features. Both missense mutations and overexpression of wild-type FUS protein can be pathogenic in human patients. To study the molecular and cellular basis by which FUS mutations and overexpression cause disease, we generated novel transgenic mice globally expressing low levels of human wild-type protein (FUS WT ) and a pathological mutation (FUS R521G ). FUS WT and FUS R521G mice that develop severe motor deficits also show neuroinflammation, denervated neuromuscular junctions, and premature death, phenocopying the human diseases. A portion of FUS R521G mice escape early lethality; these escapers have modest motor impairments and altered sociability, which correspond with a reduction of dendritic arbors and mature spines. Remarkably, only FUS R521G mice show dendritic defects; FUS WT mice do not. Activation of metabotropic glutamate receptors 1/5 in neocortical slices and isolated synaptoneurosomes increases endogenous mouse FUS and FUS WT protein levels but decreases the FUS R521G protein, providing a potential biochemical basis for the dendritic spine differences between FUS WT and FUS R521G mice.