Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations

Abstract

Mutations in the ubiquitously expressed DNA/RNA binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). While most FUS mutation studies have focused on motor neuron degeneration, little is known about wider systemic or developmental effects. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the pathogenic FUSDelta14 mutation in homozygosity. RNA sequencing of multiple organs aimed to identify pathways altered by the mutant protein in the systemic transcriptome, including metabolic tissues given the link between ALS-FTD and altered metabolism. Few genes were commonly altered across all tissues, and most genes and pathways affected were generally tissue-specific. Phenotypic assessment of mice revealed systemic metabolic alterations related to the pathway changes identified. MRI brain scans and histological characterisation revealed that homozygous FUSDelta14 brains were smaller and displayed significant morphological alterations including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with early cognitive impairment and fatal seizures. We show that the disease aetiology of FUS mutations can include both neurodevelopmental and systemic alterations.

TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43

“…This is in accordance with a previous finding from TDP-43 Q331K KI mice, although the abnormalities found here in M323K mutant mice are more severe (Lin et al, 2021). Overall, this suggests an essential role for TDP-43 in the correct development and maintenance of the central nervous system, as in the case for other hnRNP family proteins, such as FUS (Ali et al, 2023). Interestingly, MRI analysis of mutant TARDBP ALS patients have shown that TDP-43 mutations can lead to distinct cortical alterations as well as white matter abnormalities (Spinelli et al, 2022).…”

TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43

“…This is in accordance with a previous finding from TDP-43 Q331K KI mice, although the abnormalities found here in M323K mutant mice are more severe ( Lin et al, 2021 ). Overall, this suggests an essential role for TDP-43 in the correct development and maintenance of the CNS, as in the case for other hnRNP family proteins, such as FUS ( Ali et al, 2023 ). Interestingly, MRI analysis of mutant TARDBP ALS patients have shown that TDP-43 mutations can lead to distinct cortical alterations as well as white matter abnormalities ( Spinelli et al, 2022 ).…”