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FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Huang, C and Zhou, H and Tong, J and Chen, H and Liu, YJ and Wang, D and Wei, X and Xia, XG (2011) FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PLoS Genetics, 7 (3). ISSN 1553-7390

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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. © 2011 Huang et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Huang, C
Zhou, H
Tong, J
Chen, H
Liu, YJyjliu@pitt.eduYJLIU
Wang, D
Wei, X
Xia, XG
Date: 1 March 2011
Date Type: Publication
Journal or Publication Title: PLoS Genetics
Volume: 7
Number: 3
DOI or Unique Handle: 10.1371/journal.pgen.1002011
Schools and Programs: School of Medicine > Neurobiology
Refereed: Yes
ISSN: 1553-7390
MeSH Headings: Amyotrophic Lateral Sclerosis--genetics; Amyotrophic Lateral Sclerosis--metabolism; Amyotrophic Lateral Sclerosis--pathology; Animals; Disease Models, Animal; Frontotemporal Dementia--genetics; Frontotemporal Dementia--metabolism; Frontotemporal Dementia--pathology; Humans; Mutagenesis, Site-Directed; Mutation; Neuroglia--metabolism; Neurons--metabolism; RNA-Binding Protein FUS--genetics; RNA-Binding Protein FUS--metabolism; Rats; Rats, Transgenic; Ubiquitin--metabolism
Other ID: NLM PMC3048370
PubMed Central ID: PMC3048370
PubMed ID: 21408206
Date Deposited: 07 Aug 2012 15:49
Last Modified: 02 Feb 2019 16:56


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