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Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss.

ABSTRACT: FUS is an RNA-binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS-containing aggregates are often associated with concomitant loss of nuclear FUS Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell-specific CRE-mediated expression of wild-type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons.

SUBMITTER: Scekic-Zahirovic J

PROVIDER: S-EPMC4868956 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:FUS is an RNA-binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS-containing aggregates are often associated with concomitant loss of nuclear FUS. Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knock-in mice expressing mislocalized cytoplasmic FUS and complete FUS knock-out mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knock-in mice, but not FUS knock-out mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell-specific CRE-mediated expression of wild-type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons. Total RNA from brains of E18.5 knock-in (FusÎNLS/ÎNLS), and knock-out (Fus-/-) mice and their control littermates were extracted with Trizol and libraries were prepared for RNA sequencing and RNA-mediated oligonucleotide Annealing, Selection, and Ligation with Next-Generation sequencing (RASL-seq) (Li et al. 2012; Zhou et al. 2012). For the RNA-seq experiment, biological replicates were used with n=4-5 knock-in animals per group (4 wild-type and 5 homozygous FusÎNLS) and n=5 knock-out animals per group (5 wild-type and 5 homozygous Fus-/-). For the RASL-seq analysis, biological replicates were used with n=4 knock-in animals per group (4 wild-type, 4 heterozygous and 4 homozygous FusÎNLS) and n=5 animals per group (5 wild-type and 5 homozygous Fus-/- knock-out).

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Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss.

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