title: FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
abstract: 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.
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Cao
authors.initials: C
authors.lastname: Huang
authors.forename: Hongxia
authors.initials: H
authors.lastname: Zhou
authors.forename: Jianbin
authors.initials: J
authors.lastname: Tong
authors.forename: Han
authors.initials: H
authors.lastname: Chen
authors.forename: Yong-Jian
authors.initials: YJ
authors.lastname: Liu
authors.forename: Dian
authors.initials: D
authors.lastname: Wang
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Wei
authors.forename: Xu-Gang
authors.initials: XG
authors.lastname: Xia
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D034702:RNA-Binding Protein FUS; D025801:Ubiquitin