Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice

Anny Devoy; Bernadett Kalmar; Michelle Stewart; Heesoon Park; Beverley Burke; Suzanna J Noy; Yushi Redhead; Jack Humphrey; Kitty Lo; Julian Jaeger; Alan Mejia Maza; Prasanth Sivakumar; Cinzia Bertolin; Gianni Soraru; Vincent Plagnol; Linda Greensmith; Abraham Acevedo Arozena; Adrian M Isaacs; Benjamin Davies; Pietro Fratta; Elizabeth M C Fisher

doi:10.1093/brain/awx248

Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice

Anny Devoy, Bernadett Kalmar, Michelle Stewart, Heesoon Park, Beverley Burke, Suzanna J Noy, Yushi Redhead, Jack Humphrey, Kitty Lo, Julian Jaeger, Alan Mejia Maza, Prasanth Sivakumar, Cinzia Bertolin, Gianni Soraru, Vincent Plagnol, Linda Greensmith, Abraham Acevedo Arozena, Adrian M Isaacs, Benjamin Davies, Pietro FrattaElizabeth M C Fisher

Basic and Clinical Neuroscience

UCL University College London
Unit of Functional Neurosurgery, Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK; Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
MRC Harwell Institute
Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, UCL, Darwin Building, Gower Street, London WC1E 6BT, UK.
University of Padua
MRC Center for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Hospital Universitario de Canarias, Fundación Canaria de Investigación Sanitaria, Tenerife, Canary Islands, Spain.
University of Oxford

Research output: Contribution to journal › Article › peer-review

84 Citations (Scopus)

134 Downloads (Pure)

Abstract

Mutations in FUS are causative for amyotrophic lateral sclerosis with a dominant mode of inheritance. In trying to model FUS-amyotrophic lateral sclerosis (ALS) in mouse it is clear that FUS is dosage-sensitive and effects arise from overexpression per se in transgenic strains. Novel models are required that maintain physiological levels of FUS expression and that recapitulate the human disease-with progressive loss of motor neurons in heterozygous animals. Here, we describe a new humanized FUS-ALS mouse with a frameshift mutation, which fulfils both criteria: the FUS Delta14 mouse. Heterozygous animals express mutant humanized FUS protein at physiological levels and have adult onset progressive motor neuron loss and denervation of neuromuscular junctions. Additionally, we generated a novel antibody to the unique human frameshift peptide epitope, allowing specific identification of mutant FUS only. Using our new FUSDelta14 ALS mouse-antibody system we show that neurodegeneration occurs in the absence of FUS protein aggregation. FUS mislocalization increases as disease progresses, and mutant FUS accumulates at the rough endoplasmic reticulum. Further, transcriptomic analyses show progressive changes in ribosomal protein levels and mitochondrial function as early disease stages are initiated. Thus, our new physiological mouse model has provided novel insight into the early pathogenesis of FUS-ALS.

Original language	English
Pages (from-to)	2797-2805
Number of pages	9
Journal	Brain : a journal of neurology
Volume	140
Issue number	11
Early online date	7 Oct 2017
DOIs	https://doi.org/10.1093/brain/awx248
Publication status	Published - 1 Nov 2017

Keywords

Amyotrophic Lateral Sclerosis/genetics
Animals
Disease Models, Animal
Endoplasmic Reticulum, Rough/metabolism
Frameshift Mutation
Gene Dosage
Gene Expression Profiling
Gene Knock-In Techniques
Heterozygote
Humans
Mice
Mitochondria/metabolism
Motor Neurons/metabolism
Neuromuscular Junction/metabolism
Protein Aggregation, Pathological/genetics
RNA-Binding Protein FUS/genetics
Ribosomal Proteins/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/brain/awx248Licence: CC BY

Humanized mutant FUS drives progressive motor_DEVOY_Publishedonline7October2017_GOLD VoR (CC BY)Final published version, 1.17 MBLicence: CC BY

Cite this

Devoy, A., Kalmar, B., Stewart, M., Park, H., Burke, B., Noy, S. J., Redhead, Y., Humphrey, J., Lo, K., Jaeger, J., Mejia Maza, A., Sivakumar, P., Bertolin, C., Soraru, G., Plagnol, V., Greensmith, L., Acevedo Arozena, A., Isaacs, A. M., Davies, B., ... Fisher, E. M. C. (2017). Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice. Brain : a journal of neurology, 140(11), 2797-2805. https://doi.org/10.1093/brain/awx248

@article{57c6b9d482804a7e95153f29eca70861,

title = "Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice",

abstract = "Mutations in FUS are causative for amyotrophic lateral sclerosis with a dominant mode of inheritance. In trying to model FUS-amyotrophic lateral sclerosis (ALS) in mouse it is clear that FUS is dosage-sensitive and effects arise from overexpression per se in transgenic strains. Novel models are required that maintain physiological levels of FUS expression and that recapitulate the human disease-with progressive loss of motor neurons in heterozygous animals. Here, we describe a new humanized FUS-ALS mouse with a frameshift mutation, which fulfils both criteria: the FUS Delta14 mouse. Heterozygous animals express mutant humanized FUS protein at physiological levels and have adult onset progressive motor neuron loss and denervation of neuromuscular junctions. Additionally, we generated a novel antibody to the unique human frameshift peptide epitope, allowing specific identification of mutant FUS only. Using our new FUSDelta14 ALS mouse-antibody system we show that neurodegeneration occurs in the absence of FUS protein aggregation. FUS mislocalization increases as disease progresses, and mutant FUS accumulates at the rough endoplasmic reticulum. Further, transcriptomic analyses show progressive changes in ribosomal protein levels and mitochondrial function as early disease stages are initiated. Thus, our new physiological mouse model has provided novel insight into the early pathogenesis of FUS-ALS.",

keywords = "Amyotrophic Lateral Sclerosis/genetics, Animals, Disease Models, Animal, Endoplasmic Reticulum, Rough/metabolism, Frameshift Mutation, Gene Dosage, Gene Expression Profiling, Gene Knock-In Techniques, Heterozygote, Humans, Mice, Mitochondria/metabolism, Motor Neurons/metabolism, Neuromuscular Junction/metabolism, Protein Aggregation, Pathological/genetics, RNA-Binding Protein FUS/genetics, Ribosomal Proteins/genetics",

author = "Anny Devoy and Bernadett Kalmar and Michelle Stewart and Heesoon Park and Beverley Burke and Noy, {Suzanna J} and Yushi Redhead and Jack Humphrey and Kitty Lo and Julian Jaeger and {Mejia Maza}, Alan and Prasanth Sivakumar and Cinzia Bertolin and Gianni Soraru and Vincent Plagnol and Linda Greensmith and {Acevedo Arozena}, Abraham and Isaacs, {Adrian M} and Benjamin Davies and Pietro Fratta and Fisher, {Elizabeth M C}",

note = "{\textcopyright} The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.",

year = "2017",

month = nov,

day = "1",

doi = "10.1093/brain/awx248",

language = "English",

volume = "140",

pages = "2797--2805",

journal = "Brain : a journal of neurology",

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Devoy, A, Kalmar, B, Stewart, M, Park, H, Burke, B, Noy, SJ, Redhead, Y, Humphrey, J, Lo, K, Jaeger, J, Mejia Maza, A, Sivakumar, P, Bertolin, C, Soraru, G, Plagnol, V, Greensmith, L, Acevedo Arozena, A, Isaacs, AM, Davies, B, Fratta, P & Fisher, EMC 2017, 'Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice', Brain : a journal of neurology, vol. 140, no. 11, pp. 2797-2805. https://doi.org/10.1093/brain/awx248

TY - JOUR

T1 - Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice

AU - Devoy, Anny

AU - Kalmar, Bernadett

AU - Stewart, Michelle

AU - Park, Heesoon

AU - Burke, Beverley

AU - Noy, Suzanna J

AU - Redhead, Yushi

AU - Humphrey, Jack

AU - Lo, Kitty

AU - Jaeger, Julian

AU - Mejia Maza, Alan

AU - Sivakumar, Prasanth

AU - Bertolin, Cinzia

AU - Soraru, Gianni

AU - Plagnol, Vincent

AU - Greensmith, Linda

AU - Acevedo Arozena, Abraham

AU - Isaacs, Adrian M

AU - Davies, Benjamin

AU - Fratta, Pietro

AU - Fisher, Elizabeth M C

N1 - © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Mutations in FUS are causative for amyotrophic lateral sclerosis with a dominant mode of inheritance. In trying to model FUS-amyotrophic lateral sclerosis (ALS) in mouse it is clear that FUS is dosage-sensitive and effects arise from overexpression per se in transgenic strains. Novel models are required that maintain physiological levels of FUS expression and that recapitulate the human disease-with progressive loss of motor neurons in heterozygous animals. Here, we describe a new humanized FUS-ALS mouse with a frameshift mutation, which fulfils both criteria: the FUS Delta14 mouse. Heterozygous animals express mutant humanized FUS protein at physiological levels and have adult onset progressive motor neuron loss and denervation of neuromuscular junctions. Additionally, we generated a novel antibody to the unique human frameshift peptide epitope, allowing specific identification of mutant FUS only. Using our new FUSDelta14 ALS mouse-antibody system we show that neurodegeneration occurs in the absence of FUS protein aggregation. FUS mislocalization increases as disease progresses, and mutant FUS accumulates at the rough endoplasmic reticulum. Further, transcriptomic analyses show progressive changes in ribosomal protein levels and mitochondrial function as early disease stages are initiated. Thus, our new physiological mouse model has provided novel insight into the early pathogenesis of FUS-ALS.

AB - Mutations in FUS are causative for amyotrophic lateral sclerosis with a dominant mode of inheritance. In trying to model FUS-amyotrophic lateral sclerosis (ALS) in mouse it is clear that FUS is dosage-sensitive and effects arise from overexpression per se in transgenic strains. Novel models are required that maintain physiological levels of FUS expression and that recapitulate the human disease-with progressive loss of motor neurons in heterozygous animals. Here, we describe a new humanized FUS-ALS mouse with a frameshift mutation, which fulfils both criteria: the FUS Delta14 mouse. Heterozygous animals express mutant humanized FUS protein at physiological levels and have adult onset progressive motor neuron loss and denervation of neuromuscular junctions. Additionally, we generated a novel antibody to the unique human frameshift peptide epitope, allowing specific identification of mutant FUS only. Using our new FUSDelta14 ALS mouse-antibody system we show that neurodegeneration occurs in the absence of FUS protein aggregation. FUS mislocalization increases as disease progresses, and mutant FUS accumulates at the rough endoplasmic reticulum. Further, transcriptomic analyses show progressive changes in ribosomal protein levels and mitochondrial function as early disease stages are initiated. Thus, our new physiological mouse model has provided novel insight into the early pathogenesis of FUS-ALS.

KW - Amyotrophic Lateral Sclerosis/genetics

KW - Animals

KW - Disease Models, Animal

KW - Endoplasmic Reticulum, Rough/metabolism

KW - Frameshift Mutation

KW - Gene Dosage

KW - Gene Expression Profiling

KW - Gene Knock-In Techniques

KW - Heterozygote

KW - Humans

KW - Mice

KW - Mitochondria/metabolism

KW - Motor Neurons/metabolism

KW - Neuromuscular Junction/metabolism

KW - Protein Aggregation, Pathological/genetics

KW - RNA-Binding Protein FUS/genetics

KW - Ribosomal Proteins/genetics

U2 - 10.1093/brain/awx248

DO - 10.1093/brain/awx248

M3 - Article

C2 - 29053787

SN - 0006-8950

VL - 140

SP - 2797

EP - 2805

JO - Brain : a journal of neurology

JF - Brain : a journal of neurology

IS - 11

ER -

Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice

Abstract

Keywords

UN SDGs

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