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

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

UR - https://www.scopus.com/pages/publications/85032967885

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 -