| Title: |
Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations |
| Authors: |
Ali, Zeinab; Godoy-Corchuelo, Juan M; Martins-Bach, Aurea B; Garcia-Toledo, Irene; Fernández-Beltrán, Luis C; Nair, Remya R; Spring, Shoshana; Nieman, Brian J; Jimenez-Coca, Irene; Bains, Rasneer S; Forrest, Hamish; Lerch, Jason P; Miller, Karla L; Fisher, Elizabeth MC; Cunningham, Thomas J; Corrochano, Silvia |
| Source: |
Disease Models & Mechanisms , 16 (10) , Article dmm050200. (2023) |
| Publisher Information: |
The Company of Biologists |
| Publication Year: |
2023 |
| Collection: |
University College London: UCL Discovery |
| Subject Terms: |
Paediatric FUS-ALS; Multi-system metabolism; Neurodevelopmental disorder; RNA sequencing |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10181010/1/Mutation%20in%20the%20FUS%20nuclear%20localisation%20signal%20domain.pdf; https://discovery.ucl.ac.uk/id/eprint/10181010/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10181010/1/Mutation%20in%20the%20FUS%20nuclear%20localisation%20signal%20domain.pdf; https://discovery.ucl.ac.uk/id/eprint/10181010/ |
| Rights: |
open |
| Accession Number: |
edsbas.45679EB |
| Database: |
BASE |