FUS Transgenic Rats Develop the Phenotypes of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration

Fused in Sarcoma (FUS) proteinopathy is a feature of frontotemporal lobar dementia (FTLD), and mutation of the fus gene segregates with FTLD and amyotrophic lateral sclerosis (ALS). To study the consequences of mutation in the fus gene, we created transgenic rats expressing the human fus gene with or without mutation. Overexpression of a mutant (R521C substitution), but not normal, human FUS induced progressive paralysis resembling ALS. Mutant FUS transgenic rats developed progressive paralysis secondary to degeneration of motor axons and displayed a substantial loss of neurons in the cortex and hippocampus. This neuronal loss was accompanied by ubiquitin aggregation and glial reaction. While transgenic rats that overexpressed the wild-type human FUS were asymptomatic at young ages, they showed a deficit in spatial learning and memory and a significant loss of cortical and hippocampal neurons at advanced ages. These results suggest that mutant FUS is more toxic to neurons than normal FUS and that increased expression of normal FUS is sufficient to induce neuron death. Our FUS transgenic rats reproduced some phenotypes of ALS and FTLD and will provide a useful model for mechanistic studies of FUS–related diseases.
Author Summary Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are two related diseases characterized by degeneration of selected groups of neuronal cells. Neither of these diseases has a clear cause, and both are incurable at present. Mutation of the fus gene has recently been linked to these two diseases. Here, we describe a novel rat model that expresses a mutated form of the human fus gene and manifests the phenotypes and pathological features of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Establishment of this FUS transgenic rat model will allow not only for mechanistic study of FUS–related diseases, but also for quick development of therapies for these devastating diseases.