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

Christophe Verbeeck, Qiudong Deng, Mariely Dejesus-Hernandez, Georgia Taylor, Carolina Ceballos-Diaz, Jannet Kocerha, Todd Golde, Pritam Das, Rosa V Rademakers, Dennis W Dickson, Thomas Kukar

Research output: Contribution to journalArticle

44 Citations (Scopus)

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.

Original languageEnglish (US)
Article number53
JournalMolecular Neurodegeneration
Volume7
Issue number1
DOIs
StatePublished - 2012

Fingerprint

Sarcoma
Mutation
Amyotrophic Lateral Sclerosis
Dementia
Inclusion Bodies
Neuropathology
Poly(A)-Binding Proteins
Frontotemporal Lobar Degeneration
RNA-Binding Proteins
Cytomegalovirus Infections
RNA
Transgenic Mice
Brain
Cytoplasm
Nuclear Localization Signals
Dependovirus
Critical Pathways
Intermediate Filaments
Ubiquitin

Keywords

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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis. / Verbeeck, Christophe; Deng, Qiudong; Dejesus-Hernandez, Mariely; Taylor, Georgia; Ceballos-Diaz, Carolina; Kocerha, Jannet; Golde, Todd; Das, Pritam; Rademakers, Rosa V; Dickson, Dennis W; Kukar, Thomas.

In: Molecular Neurodegeneration, Vol. 7, No. 1, 53, 2012.

Research output: Contribution to journalArticle

Verbeeck, Christophe ; Deng, Qiudong ; Dejesus-Hernandez, Mariely ; Taylor, Georgia ; Ceballos-Diaz, Carolina ; Kocerha, Jannet ; Golde, Todd ; Das, Pritam ; Rademakers, Rosa V ; Dickson, Dennis W ; Kukar, Thomas. / Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis. In: Molecular Neurodegeneration. 2012 ; Vol. 7, No. 1.
@article{606848aa8a9847ea861c309f8241e601,
title = "Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis",
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 = "α-internexin, Adeno-associated virus, Amyotrophic lateral sclerosis, Frontotemporal lobar degeneration, Fused in sarcoma proteinopathies, Neuronal cytoplasmic inclusions, p62/SQSTM1, PABP-1, RNA dysfunction, Stress granules, Transgenic mouse models, Ubiquitin",
author = "Christophe Verbeeck and Qiudong Deng and Mariely Dejesus-Hernandez and Georgia Taylor and Carolina Ceballos-Diaz and Jannet Kocerha and Todd Golde and Pritam Das and Rademakers, {Rosa V} and Dickson, {Dennis W} and Thomas Kukar",
year = "2012",
doi = "10.1186/1750-1326-7-53",
language = "English (US)",
volume = "7",
journal = "Molecular Neurodegeneration",
issn = "1750-1326",
publisher = "BioMed Central",
number = "1",

}

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 V

AU - Dickson, Dennis W

AU - Kukar, Thomas

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 - α-internexin

KW - Adeno-associated virus

KW - Amyotrophic lateral sclerosis

KW - Frontotemporal lobar degeneration

KW - Fused in sarcoma proteinopathies

KW - Neuronal cytoplasmic inclusions

KW - p62/SQSTM1

KW - PABP-1

KW - RNA dysfunction

KW - Stress granules

KW - Transgenic mouse models

KW - Ubiquitin

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

VL - 7

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

SN - 1750-1326

IS - 1

M1 - 53

ER -