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Innervation and cargo-specific axonal transport impairments in FUS-ALS mice with gain and loss of function [RNA-seq]

ABSTRACT: Mutations in the RNA-binding protein FUS cause aggressive, early-onset forms of amyotrophic lateral sclerosis (ALS), leading to the progressive degeneration of the neuromuscular system. These mutations drive nuclear depletion and cytoplasmic mislocalisation of FUS, resulting in both loss and gain of function. We investigated these mechanisms and their impact on key pathophysiological processes in vivo, using a novel FUS-ALS mouse model. Adult mice presented widespread transcriptomic alterations consistent with nuclear loss of function, while translatome analysis revealed specific deficits associated with aberrant FUS-dependent cytoplasmic partitioning and gain of function. Mutant FUS expression selectively impaired neuromuscular junction (NMJ) innervation in FUS-ALS females. However, NMJ reinnervation following sciatic nerve crush was equally perturbed in homozygous mutants of both sexes, indicating impaired regeneration and damage responses. Additionally, we observed cargo-specific alterations in axonal transport, a process critical for neuronal function and maintenance; in vivo mitochondrial transport was impaired in homozygous FUS-ALS mice, whereas the retrograde transport of signalling endosomes was again only affected in mutant females, strengthening the link between endosomal transport impairment and NMJ denervation in ALS. Altogether, our findings establish FUS-ALS homozygous mice as a valuable model for investigating early cellular impairments driving ALS pathology, and identify broader and sex-dependent motor neuron dysfunction in FUS-ALS pathogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE298456 | GEO | 2025/05/29

REPOSITORIES: GEO

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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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Innervation and cargo-specific axonal transport impairments in FUS-ALS mice with gain and loss of function [RNA-seq]

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