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ALS/FTD-Linked Mutation in FUS Suppresses Intra-axonal Protein Synthesis and Drives Disease Without Nuclear Loss-of-Function of FUS

Through the generation of humanized FUS mice expressing full-length human FUS, we identify that when expressed at near endogenous murine FUS levels, both wild-type and ALS-causing and frontotemporal dementia (FTD)-causing mutations complement the essential function(s) of murine FUS. Replacement of m... Full description

Journal Title: Neuron 2018-11-21, Vol.100 (4), p.816-830.e7
Main Author: López-Erauskin, Jone
Other Authors: Tadokoro, Takahiro , Baughn, Michael W , Myers, Brian , McAlonis-Downes, Melissa , Chillon-Marinas, Carlos , Asiaban, Joshua N , Artates, Jonathan , Bui, Anh T , Vetto, Anne P , Lee, Sandra K , Le, Ai Vy , Sun, Ying , Jambeau, Mélanie , Boubaker, Jihane , Swing, Deborah , Qiu, Jinsong , Hicks, Geoffrey G , Ouyang, Zhengyu , Fu, Xiang-Dong , Tessarollo, Lino , Ling, Shuo-Chien , Parone, Philippe A , Shaw, Christopher E , Marsala, Martin , Lagier-Tourenne, Clotilde , Cleveland, Don W , Da Cruz, Sandrine
Format: Electronic Article Electronic Article
Language: English
Subjects:
Age
ALS
FTD
FUS
RNA
TLS
Quelle: Alma/SFX Local Collection
Publisher: United States: Elsevier Inc
ID: ISSN: 0896-6273
Link: https://www.ncbi.nlm.nih.gov/pubmed/30344044
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6277851
title: ALS/FTD-Linked Mutation in FUS Suppresses Intra-axonal Protein Synthesis and Drives Disease Without Nuclear Loss-of-Function of FUS
format: Article
creator:
  • López-Erauskin, Jone
  • Tadokoro, Takahiro
  • Baughn, Michael W
  • Myers, Brian
  • McAlonis-Downes, Melissa
  • Chillon-Marinas, Carlos
  • Asiaban, Joshua N
  • Artates, Jonathan
  • Bui, Anh T
  • Vetto, Anne P
  • Lee, Sandra K
  • Le, Ai Vy
  • Sun, Ying
  • Jambeau, Mélanie
  • Boubaker, Jihane
  • Swing, Deborah
  • Qiu, Jinsong
  • Hicks, Geoffrey G
  • Ouyang, Zhengyu
  • Fu, Xiang-Dong
  • Tessarollo, Lino
  • Ling, Shuo-Chien
  • Parone, Philippe A
  • Shaw, Christopher E
  • Marsala, Martin
  • Lagier-Tourenne, Clotilde
  • Cleveland, Don W
  • Da Cruz, Sandrine
subjects:
  • Age
  • ALS
  • Amyotrophic Lateral Sclerosis
  • Amyotrophic Lateral Sclerosis - genetics
  • Amyotrophic Lateral Sclerosis - metabolism
  • Amyotrophic Lateral Sclerosis - pathology
  • Animals
  • Article
  • axonal translation
  • Axons - pathology
  • Axons - physiology
  • Behavior
  • Binding proteins
  • Cells, Cultured
  • Chaperones
  • Cognitive ability
  • Dementia
  • Dementia disorders
  • Female
  • Frontotemporal dementia
  • Frontotemporal Dementia - genetics
  • Frontotemporal Dementia - metabolism
  • Frontotemporal Dementia - pathology
  • FTD
  • FUS
  • FUS protein
  • Gene expression
  • Genetic aspects
  • Genetic translation
  • Hippocampus
  • Hippocampus - metabolism
  • Hippocampus - pathology
  • Humans
  • Ion channels
  • Localization
  • Loss of Function Mutation - genetics
  • Male
  • Medical research
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Nerves
  • Nervous system diseases
  • neurodegenerative disease
  • Neurons
  • Pregnancy
  • Protein binding
  • Protein biosynthesis
  • Protein Biosynthesis - physiology
  • protein synthesis
  • Proteins
  • RNA
  • RNA-Binding Protein FUS - biosynthesis
  • RNA-Binding Protein FUS - genetics
  • RNA-binding proteins
  • Software
  • Spinal cord
  • Splicing
  • TLS
  • Toxicity
ispartof: Neuron, 2018-11-21, Vol.100 (4), p.816-830.e7
description: Through the generation of humanized FUS mice expressing full-length human FUS, we identify that when expressed at near endogenous murine FUS levels, both wild-type and ALS-causing and frontotemporal dementia (FTD)-causing mutations complement the essential function(s) of murine FUS. Replacement of murine FUS with mutant, but not wild-type, human FUS causes stress-mediated induction of chaperones, decreased expression of ion channels and transporters essential for synaptic function, and reduced synaptic activity without loss of nuclear FUS or its cytoplasmic aggregation. Most strikingly, accumulation of mutant human FUS is shown to activate an integrated stress response and to inhibit local, intra-axonal protein synthesis in hippocampal neurons and sciatic nerves. Collectively, our evidence demonstrates that human ALS/FTD-linked mutations in FUS induce a gain of toxicity that includes stress-mediated suppression in intra-axonal translation, synaptic dysfunction, and progressive age-dependent motor and cognitive disease without cytoplasmic aggregation, altered nuclear localization, or aberrant splicing of FUS-bound pre-mRNAs. [Display omitted] [Display omitted] •Toxicity, not loss of function, of ALS/FTD-linked mutant FUS drives disease•Intra-axonal protein synthesis is inhibited by ALS/FTD-causing mutants in FUS•Toxicity from ALS/FTD-linked mutants in FUS induces an integrated stress response•ALS/FTD mutants in FUS reduce synaptic activity without loss of nuclear FUS Mutations in FUS are causative of ALS and frontotemporal dementia (FTD). López-Erauskin et al. show that disease-causing mutant FUS inhibits intra-axonal protein synthesis and provokes hippocampal synaptic loss and dysfunction without loss of nuclear FUS function or FUS aggregation.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0896-6273
fulltext: fulltext
issn:
  • 0896-6273
  • 1097-4199
url: Link


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titleALS/FTD-Linked Mutation in FUS Suppresses Intra-axonal Protein Synthesis and Drives Disease Without Nuclear Loss-of-Function of FUS
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creatorLópez-Erauskin, Jone ; Tadokoro, Takahiro ; Baughn, Michael W ; Myers, Brian ; McAlonis-Downes, Melissa ; Chillon-Marinas, Carlos ; Asiaban, Joshua N ; Artates, Jonathan ; Bui, Anh T ; Vetto, Anne P ; Lee, Sandra K ; Le, Ai Vy ; Sun, Ying ; Jambeau, Mélanie ; Boubaker, Jihane ; Swing, Deborah ; Qiu, Jinsong ; Hicks, Geoffrey G ; Ouyang, Zhengyu ; Fu, Xiang-Dong ; Tessarollo, Lino ; Ling, Shuo-Chien ; Parone, Philippe A ; Shaw, Christopher E ; Marsala, Martin ; Lagier-Tourenne, Clotilde ; Cleveland, Don W ; Da Cruz, Sandrine
creatorcontribLópez-Erauskin, Jone ; Tadokoro, Takahiro ; Baughn, Michael W ; Myers, Brian ; McAlonis-Downes, Melissa ; Chillon-Marinas, Carlos ; Asiaban, Joshua N ; Artates, Jonathan ; Bui, Anh T ; Vetto, Anne P ; Lee, Sandra K ; Le, Ai Vy ; Sun, Ying ; Jambeau, Mélanie ; Boubaker, Jihane ; Swing, Deborah ; Qiu, Jinsong ; Hicks, Geoffrey G ; Ouyang, Zhengyu ; Fu, Xiang-Dong ; Tessarollo, Lino ; Ling, Shuo-Chien ; Parone, Philippe A ; Shaw, Christopher E ; Marsala, Martin ; Lagier-Tourenne, Clotilde ; Cleveland, Don W ; Da Cruz, Sandrine
descriptionThrough the generation of humanized FUS mice expressing full-length human FUS, we identify that when expressed at near endogenous murine FUS levels, both wild-type and ALS-causing and frontotemporal dementia (FTD)-causing mutations complement the essential function(s) of murine FUS. Replacement of murine FUS with mutant, but not wild-type, human FUS causes stress-mediated induction of chaperones, decreased expression of ion channels and transporters essential for synaptic function, and reduced synaptic activity without loss of nuclear FUS or its cytoplasmic aggregation. Most strikingly, accumulation of mutant human FUS is shown to activate an integrated stress response and to inhibit local, intra-axonal protein synthesis in hippocampal neurons and sciatic nerves. Collectively, our evidence demonstrates that human ALS/FTD-linked mutations in FUS induce a gain of toxicity that includes stress-mediated suppression in intra-axonal translation, synaptic dysfunction, and progressive age-dependent motor and cognitive disease without cytoplasmic aggregation, altered nuclear localization, or aberrant splicing of FUS-bound pre-mRNAs. [Display omitted] [Display omitted] •Toxicity, not loss of function, of ALS/FTD-linked mutant FUS drives disease•Intra-axonal protein synthesis is inhibited by ALS/FTD-causing mutants in FUS•Toxicity from ALS/FTD-linked mutants in FUS induces an integrated stress response•ALS/FTD mutants in FUS reduce synaptic activity without loss of nuclear FUS Mutations in FUS are causative of ALS and frontotemporal dementia (FTD). López-Erauskin et al. show that disease-causing mutant FUS inhibits intra-axonal protein synthesis and provokes hippocampal synaptic loss and dysfunction without loss of nuclear FUS function or FUS aggregation.
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1EISSN: 1097-4199
2DOI: 10.1016/j.neuron.2018.09.044
3PMID: 30344044
languageeng
publisherUnited States: Elsevier Inc
subjectAge ; ALS ; Amyotrophic Lateral Sclerosis ; Amyotrophic Lateral Sclerosis - genetics ; Amyotrophic Lateral Sclerosis - metabolism ; Amyotrophic Lateral Sclerosis - pathology ; Animals ; Article ; axonal translation ; Axons - pathology ; Axons - physiology ; Behavior ; Binding proteins ; Cells, Cultured ; Chaperones ; Cognitive ability ; Dementia ; Dementia disorders ; Female ; Frontotemporal dementia ; Frontotemporal Dementia - genetics ; Frontotemporal Dementia - metabolism ; Frontotemporal Dementia - pathology ; FTD ; FUS ; FUS protein ; Gene expression ; Genetic aspects ; Genetic translation ; Hippocampus ; Hippocampus - metabolism ; Hippocampus - pathology ; Humans ; Ion channels ; Localization ; Loss of Function Mutation - genetics ; Male ; Medical research ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Nerves ; Nervous system diseases ; neurodegenerative disease ; Neurons ; Pregnancy ; Protein binding ; Protein biosynthesis ; Protein Biosynthesis - physiology ; protein synthesis ; Proteins ; RNA ; RNA-Binding Protein FUS - biosynthesis ; RNA-Binding Protein FUS - genetics ; RNA-binding proteins ; Software ; Spinal cord ; Splicing ; TLS ; Toxicity
ispartofNeuron, 2018-11-21, Vol.100 (4), p.816-830.e7
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02018 The Author(s)
1Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
2COPYRIGHT 2018 Elsevier B.V.
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0López-Erauskin, Jone
1Tadokoro, Takahiro
2Baughn, Michael W
3Myers, Brian
4McAlonis-Downes, Melissa
5Chillon-Marinas, Carlos
6Asiaban, Joshua N
7Artates, Jonathan
8Bui, Anh T
9Vetto, Anne P
10Lee, Sandra K
11Le, Ai Vy
12Sun, Ying
13Jambeau, Mélanie
14Boubaker, Jihane
15Swing, Deborah
16Qiu, Jinsong
17Hicks, Geoffrey G
18Ouyang, Zhengyu
19Fu, Xiang-Dong
20Tessarollo, Lino
21Ling, Shuo-Chien
22Parone, Philippe A
23Shaw, Christopher E
24Marsala, Martin
25Lagier-Tourenne, Clotilde
26Cleveland, Don W
27Da Cruz, Sandrine
title
0ALS/FTD-Linked Mutation in FUS Suppresses Intra-axonal Protein Synthesis and Drives Disease Without Nuclear Loss-of-Function of FUS
1Neuron
addtitleNeuron
descriptionThrough the generation of humanized FUS mice expressing full-length human FUS, we identify that when expressed at near endogenous murine FUS levels, both wild-type and ALS-causing and frontotemporal dementia (FTD)-causing mutations complement the essential function(s) of murine FUS. Replacement of murine FUS with mutant, but not wild-type, human FUS causes stress-mediated induction of chaperones, decreased expression of ion channels and transporters essential for synaptic function, and reduced synaptic activity without loss of nuclear FUS or its cytoplasmic aggregation. Most strikingly, accumulation of mutant human FUS is shown to activate an integrated stress response and to inhibit local, intra-axonal protein synthesis in hippocampal neurons and sciatic nerves. Collectively, our evidence demonstrates that human ALS/FTD-linked mutations in FUS induce a gain of toxicity that includes stress-mediated suppression in intra-axonal translation, synaptic dysfunction, and progressive age-dependent motor and cognitive disease without cytoplasmic aggregation, altered nuclear localization, or aberrant splicing of FUS-bound pre-mRNAs. [Display omitted] [Display omitted] •Toxicity, not loss of function, of ALS/FTD-linked mutant FUS drives disease•Intra-axonal protein synthesis is inhibited by ALS/FTD-causing mutants in FUS•Toxicity from ALS/FTD-linked mutants in FUS induces an integrated stress response•ALS/FTD mutants in FUS reduce synaptic activity without loss of nuclear FUS Mutations in FUS are causative of ALS and frontotemporal dementia (FTD). López-Erauskin et al. show that disease-causing mutant FUS inhibits intra-axonal protein synthesis and provokes hippocampal synaptic loss and dysfunction without loss of nuclear FUS function or FUS aggregation.
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1ALS
2Amyotrophic Lateral Sclerosis
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4Amyotrophic Lateral Sclerosis - metabolism
5Amyotrophic Lateral Sclerosis - pathology
6Animals
7Article
8axonal translation
9Axons - pathology
10Axons - physiology
11Behavior
12Binding proteins
13Cells, Cultured
14Chaperones
15Cognitive ability
16Dementia
17Dementia disorders
18Female
19Frontotemporal dementia
20Frontotemporal Dementia - genetics
21Frontotemporal Dementia - metabolism
22Frontotemporal Dementia - pathology
23FTD
24FUS
25FUS protein
26Gene expression
27Genetic aspects
28Genetic translation
29Hippocampus
30Hippocampus - metabolism
31Hippocampus - pathology
32Humans
33Ion channels
34Localization
35Loss of Function Mutation - genetics
36Male
37Medical research
38Mice
39Mice, Inbred C57BL
40Mice, Transgenic
41Mutation
42Nerves
43Nervous system diseases
44neurodegenerative disease
45Neurons
46Pregnancy
47Protein binding
48Protein biosynthesis
49Protein Biosynthesis - physiology
50protein synthesis
51Proteins
52RNA
53RNA-Binding Protein FUS - biosynthesis
54RNA-Binding Protein FUS - genetics
55RNA-binding proteins
56Software
57Spinal cord
58Splicing
59TLS
60Toxicity
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4McAlonis-Downes, Melissa
5Chillon-Marinas, Carlos
6Asiaban, Joshua N
7Artates, Jonathan
8Bui, Anh T
9Vetto, Anne P
10Lee, Sandra K
11Le, Ai Vy
12Sun, Ying
13Jambeau, Mélanie
14Boubaker, Jihane
15Swing, Deborah
16Qiu, Jinsong
17Hicks, Geoffrey G
18Ouyang, Zhengyu
19Fu, Xiang-Dong
20Tessarollo, Lino
21Ling, Shuo-Chien
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23Shaw, Christopher E
24Marsala, Martin
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titleALS/FTD-Linked Mutation in FUS Suppresses Intra-axonal Protein Synthesis and Drives Disease Without Nuclear Loss-of-Function of FUS
authorLópez-Erauskin, Jone ; Tadokoro, Takahiro ; Baughn, Michael W ; Myers, Brian ; McAlonis-Downes, Melissa ; Chillon-Marinas, Carlos ; Asiaban, Joshua N ; Artates, Jonathan ; Bui, Anh T ; Vetto, Anne P ; Lee, Sandra K ; Le, Ai Vy ; Sun, Ying ; Jambeau, Mélanie ; Boubaker, Jihane ; Swing, Deborah ; Qiu, Jinsong ; Hicks, Geoffrey G ; Ouyang, Zhengyu ; Fu, Xiang-Dong ; Tessarollo, Lino ; Ling, Shuo-Chien ; Parone, Philippe A ; Shaw, Christopher E ; Marsala, Martin ; Lagier-Tourenne, Clotilde ; Cleveland, Don W ; Da Cruz, Sandrine
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1ALS
2Amyotrophic Lateral Sclerosis
3Amyotrophic Lateral Sclerosis - genetics
4Amyotrophic Lateral Sclerosis - metabolism
5Amyotrophic Lateral Sclerosis - pathology
6Animals
7Article
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9Axons - pathology
10Axons - physiology
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12Binding proteins
13Cells, Cultured
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15Cognitive ability
16Dementia
17Dementia disorders
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19Frontotemporal dementia
20Frontotemporal Dementia - genetics
21Frontotemporal Dementia - metabolism
22Frontotemporal Dementia - pathology
23FTD
24FUS
25FUS protein
26Gene expression
27Genetic aspects
28Genetic translation
29Hippocampus
30Hippocampus - metabolism
31Hippocampus - pathology
32Humans
33Ion channels
34Localization
35Loss of Function Mutation - genetics
36Male
37Medical research
38Mice
39Mice, Inbred C57BL
40Mice, Transgenic
41Mutation
42Nerves
43Nervous system diseases
44neurodegenerative disease
45Neurons
46Pregnancy
47Protein binding
48Protein biosynthesis
49Protein Biosynthesis - physiology
50protein synthesis
51Proteins
52RNA
53RNA-Binding Protein FUS - biosynthesis
54RNA-Binding Protein FUS - genetics
55RNA-binding proteins
56Software
57Spinal cord
58Splicing
59TLS
60Toxicity
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7Artates, Jonathan
8Bui, Anh T
9Vetto, Anne P
10Lee, Sandra K
11Le, Ai Vy
12Sun, Ying
13Jambeau, Mélanie
14Boubaker, Jihane
15Swing, Deborah
16Qiu, Jinsong
17Hicks, Geoffrey G
18Ouyang, Zhengyu
19Fu, Xiang-Dong
20Tessarollo, Lino
21Ling, Shuo-Chien
22Parone, Philippe A
23Shaw, Christopher E
24Marsala, Martin
25Lagier-Tourenne, Clotilde
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0López-Erauskin, Jone
1Tadokoro, Takahiro
2Baughn, Michael W
3Myers, Brian
4McAlonis-Downes, Melissa
5Chillon-Marinas, Carlos
6Asiaban, Joshua N
7Artates, Jonathan
8Bui, Anh T
9Vetto, Anne P
10Lee, Sandra K
11Le, Ai Vy
12Sun, Ying
13Jambeau, Mélanie
14Boubaker, Jihane
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16Qiu, Jinsong
17Hicks, Geoffrey G
18Ouyang, Zhengyu
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20Tessarollo, Lino
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atitleALS/FTD-Linked Mutation in FUS Suppresses Intra-axonal Protein Synthesis and Drives Disease Without Nuclear Loss-of-Function of FUS
jtitleNeuron
addtitleNeuron
date2018-11-21
risdate2018
volume100
issue4
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pages816-830.e7
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notes
0Lead Contact
1Present address: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
2Present address: Program in Neuroscience and Behavior Disorders, Duke-NUS Graduate Medical School, Singapore
3Present address: Department of Physiology, National University of Singapore, 117549, Singapore
4Present address: Fate Therapeutics, 3535 General Atomics Court, San Diego, CA 9212, USA
abstractThrough the generation of humanized FUS mice expressing full-length human FUS, we identify that when expressed at near endogenous murine FUS levels, both wild-type and ALS-causing and frontotemporal dementia (FTD)-causing mutations complement the essential function(s) of murine FUS. Replacement of murine FUS with mutant, but not wild-type, human FUS causes stress-mediated induction of chaperones, decreased expression of ion channels and transporters essential for synaptic function, and reduced synaptic activity without loss of nuclear FUS or its cytoplasmic aggregation. Most strikingly, accumulation of mutant human FUS is shown to activate an integrated stress response and to inhibit local, intra-axonal protein synthesis in hippocampal neurons and sciatic nerves. Collectively, our evidence demonstrates that human ALS/FTD-linked mutations in FUS induce a gain of toxicity that includes stress-mediated suppression in intra-axonal translation, synaptic dysfunction, and progressive age-dependent motor and cognitive disease without cytoplasmic aggregation, altered nuclear localization, or aberrant splicing of FUS-bound pre-mRNAs. [Display omitted] [Display omitted] •Toxicity, not loss of function, of ALS/FTD-linked mutant FUS drives disease•Intra-axonal protein synthesis is inhibited by ALS/FTD-causing mutants in FUS•Toxicity from ALS/FTD-linked mutants in FUS induces an integrated stress response•ALS/FTD mutants in FUS reduce synaptic activity without loss of nuclear FUS Mutations in FUS are causative of ALS and frontotemporal dementia (FTD). López-Erauskin et al. show that disease-causing mutant FUS inhibits intra-axonal protein synthesis and provokes hippocampal synaptic loss and dysfunction without loss of nuclear FUS function or FUS aggregation.
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pubElsevier Inc
pmid30344044
doi10.1016/j.neuron.2018.09.044
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