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

Ali, Zeinab; Godoy-Corchuelo, Juan M; Martins-Bach, Aurea B; Garcia-Toledo, Irene; Fernández-Beltrán, Luis C; Nair, Remya R; Spring, Shoshana; ... Corrochano, Silvia; + view all (2023) Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations. Disease Models & Mechanisms , 16 (10) , Article dmm050200. 10.1242/dmm.050200. Green open access

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Abstract

Variants in the ubiquitously expressed DNA/RNA-binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). 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-frontotemporal dementia 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. Magnetic resonance imaging brain scans and histological characterisation revealed that homozygous FUSDelta14 brains were smaller than heterozygous and wild-type brains and displayed significant morphological alterations, including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with early cognitive impairment and fatal seizures. These findings show that the disease aetiology of FUS variants can include both neurodevelopmental and systemic alterations.

Type: Article
Title: Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1242/dmm.050200
Publisher version: https://doi.org/10.1242/dmm.050200
Language: English
Additional information: Copyright © 2023. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Keywords: Paediatric FUS-ALS, Multi-system metabolism, Neurodevelopmental disorder, RNA sequencing
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10181010
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