Open Access Highly Accessed Research article

Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis

Christophe Verbeeck1, Qiudong Deng2, Mariely DeJesus-Hernandez1, Georgia Taylor2, Carolina Ceballos-Diaz3, Jannet Kocerha4, Todd Golde3, Pritam Das1, Rosa Rademakers1, Dennis W Dickson1 and Thomas Kukar2*

Author Affiliations

1 Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

2 Department of Pharmacology and Neurology, Emory University School of Medicine, Atlanta, GA, USA

3 Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA

4 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA

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Molecular Neurodegeneration 2012, 7:53  doi:10.1186/1750-1326-7-53

Published: 10 October 2012

Abstract

Background

Mutations in the gene encoding the RNA-binding protein fused in sarcoma (FUS) can cause familial and sporadic amyotrophic lateral sclerosis (ALS) and rarely frontotemproal dementia (FTD). FUS accumulates in neuronal cytoplasmic inclusions (NCIs) in ALS patients with FUS mutations. FUS is also a major pathologic marker for a group of less common forms of frontotemporal lobar degeneration (FTLD), which includes atypical FTLD with ubiquitinated inclusions (aFTLD-U), neuronal intermediate filament inclusion disease (NIFID) and basophilic inclusion body disease (BIBD). These diseases are now called FUS proteinopathies, because they share this disease marker. It is unknown how FUS mutations cause disease and the role of FUS in FTD-FUS cases, which do not have FUS mutations. In this paper we report the development of somatic brain transgenic (SBT) mice using recombinant adeno-associated virus (rAAV) to investigate how FUS mutations lead to neurodegeneration.

Results

We compared SBT mice expressing wild-type human FUS (FUSWT), and two ALS-linked mutations: FUSR521C and FUSΔ14, which lacks the nuclear localization signal. Both FUS mutants accumulated in the cytoplasm relative to FUSWT. The degree of this shift correlated with the severity of the FUS mutation as reflected by disease onset in humans. Mice expressing the most aggressive mutation, FUSΔ14, recapitulated many aspects of FUS proteinopathies, including insoluble FUS, basophilic and eosiniphilic NCIs, and other pathologic markers, including ubiquitin, p62/SQSTM1, α-internexin, and the poly-adenylate(A)-binding protein 1 (PABP-1). However, TDP-43 did not localize to inclusions.

Conclusions

Our data supports the hypothesis that ALS or FTD-linked FUS mutations cause neurodegeneration by increasing cyotplasmic FUS. Accumulation of FUS in the cytoplasm may retain RNA targets and recruit additional RNA-binding proteins, such as PABP-1, into stress-granule like aggregates that coalesce into permanent inclusions that could negatively affect RNA metabolism. Identification of mutations in other genes that cause ALS/FTD, such as C9ORF72, sentaxin, and angiogenin, lends support to the idea that defective RNA metabolism is a critical pathogenic pathway. The SBT FUS mice described here will provide a valuable platform for dissecting the pathogenic mechanism of FUS mutations, define the relationship between FTD and ALS-FUS, and help identify therapeutic targets that are desperately needed for these devastating neurodegenerative disorders.

Keywords:
Amyotrophic lateral sclerosis; Frontotemporal lobar degeneration; Fused in sarcoma proteinopathies; Transgenic mouse models; Adeno-associated virus; Neuronal cytoplasmic inclusions; Ubiquitin; p62/SQSTM1; α-internexin; PABP-1; Stress granules; RNA dysfunction