TY - JOUR
T1 - Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis
AU - Verbeeck, Christophe
AU - Deng, Qiudong
AU - Dejesus-Hernandez, Mariely
AU - Taylor, Georgia
AU - Ceballos-Diaz, Carolina
AU - Kocerha, Jannet
AU - Golde, Todd
AU - Das, Pritam
AU - Rademakers, Rosa
AU - Dickson, Dennis W.
AU - Kukar, Thomas
N1 - Funding Information:
The authors thank Monica Castanedes-Casey, Virginia Phillips and Linda Rousseau for their excellent histological and immunohistochemical support. Dr. Gerry Shaw at the University of Florida kindly provided the monoclonal antibody against α-internexin. TK is supported by the National Institutes of Health grants (P30NS069289 and P50AG016574-13). RR is supported by the National Institutes of Health grants (P50AG016574-13 and R01NS065782). QD is supported by National institutes of Health training grant T32 “Training and translational research in Neurology” (2T32 NS 007480). This research project was supported in part by the Microscopy Core Facility of the Emory Neuroscience NINDS Core Facilities grant (P30NS055077).
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Adeno-associated virus
KW - Amyotrophic lateral sclerosis
KW - Frontotemporal lobar degeneration
KW - Fused in sarcoma proteinopathies
KW - Neuronal cytoplasmic inclusions
KW - PABP-1
KW - RNA dysfunction
KW - Stress granules
KW - Transgenic mouse models
KW - Ubiquitin
KW - p62/SQSTM1
KW - α-internexin
UR - http://www.scopus.com/inward/record.url?scp=84867217368&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867217368&partnerID=8YFLogxK
U2 - 10.1186/1750-1326-7-53
DO - 10.1186/1750-1326-7-53
M3 - Article
C2 - 23046583
AN - SCOPUS:84867217368
SN - 1750-1326
VL - 7
JO - Molecular neurodegeneration
JF - Molecular neurodegeneration
IS - 1
M1 - 53
ER -