| Title: |
FUS Mislocalization Rewires a Cortical Gene Network to Drive Cognitive and Behavioral Impairment in ALS ; La mauvaise localisation de la protéine FUS modifie le réseau génétique cortical, entraînant des troubles cognitifs et comportementaux dans la SLA. |
| Authors: |
Cassel, Raphaelle; Lorenc, Félicie; Bombardier, Aurélie; de Tapia, Claudia; Dieterle, Stéphane; Gouveia Roque, Cláudio; Jackson, Christopher, A; Stuart-Lopez, Geoffrey; Rouaux, Caroline; Guillot, Simon, J; Birling, Marie-Christine; Kessler, Pascal; Grassano, Maurizio; Traynor, Bryan; Chio, Adriano; Roy, Raju; Shorter, James; Waldron, Fergal, M; Gregory, Jenna, M; Phatnani, Hemali; Dupuis, Luc; Megat, Salim |
| Contributors: |
Equipe "SLA-DFT" de l'U1329; Neuroscience et Psychiatrie Translationnelle de Strasbourg (STEP); Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM); New York Genome Center New York; New York Genome Center; Institut Clinique de la Souris (ICS); Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Centre de Recherche en Biomédecine de Strasbourg (CRBS); Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM); Department of Oncology University of Turin; Università degli studi di Torino = University of Turin (UNITO); National Institute on Aging Bethesda, USA (NIA); National Institutes of Health Bethesda, MD, USA (NIH); Johns Hopkins University School of Medicine Baltimore; National Institute of Neurological Disorders and Stroke Bethesda (NINDS); National Center for Advancing Translational Sciences (NCATS); Perelman School of Medicine; University of Pennsylvania Philadelphia; University of Aberdeen; Institute of Medical Sciences; University of Aberdeen-School of Medical Sciences; Columbia University New York; Center for Translational and Computational Neuroimmunology New York, NY, États-Unis (CTCN); Department of Neurology New York, NY, États-Unis; Columbia University Medical Center (CUMC); Columbia University New York -Columbia University New York -Columbia University Medical Center (CUMC); Columbia University New York -Columbia University New York; ANR-16-CE92-0031,EpiFUS,Rôle de FUS dans la régulation des modifications épigénétiques : conséquences pour la sclérose latérale amyotrophique et la démence frontotemporale(2016); ANR-19-CE17-0016,SPREADALS,Propagation et toxicité des facteurs pathogéniques de la sclérose latérale amyotrophique(2019); ANR-20-CE17-0008,CA-Ts,Rôle des microsatellites à répétition CA dans les maladies liées à FUS et TDP-43(2020); ANR-21-CE17-0039,MiRrOR,Etude du mode d'action de la flunarizine impliquant les microRNA et leurs cibles dans les maladies rares du motoneurone(2021); ANR-24-CE37-4064,Wake-ALS,Circuits de l'éveil dans la sclérose latérale amyotrophique: importance translationnelle(2024); ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010); ANR-20-SFRI-0012,STRAT'US,Façonner les talents en formation et en recherche à l'Université de Strasbourg(2020) |
| Source: |
https://inserm.hal.science/inserm-05509094 ; 2026. |
| Publisher Information: |
CCSD |
| Publication Year: |
2026 |
| Collection: |
Inserm: HAL (Institut national de la santé et de la recherche médicale) |
| Subject Terms: |
single cell biology; genetics; mouse models; behavioral impairment; cognitive impairment; fronto-temporal dementia; Amyotrophic lateral sclerosis; [SCCO.NEUR]Cognitive science/Neuroscience |
| Description: |
International audience ; Summary Cognitive and behavioral impairment affects up to half of individuals with amyotrophic lateral sclerosis (ALS), but their molecular origin remains unresolved. Here, we identify mislocalization of the RNA-binding protein FUS in cortical neurons as a defining feature in ALS patients with cognitive impairment (ALS-ci). Selective mislocalization of FUS in adult cortical projection neurons in mice is sufficient to trigger ALS-ci– and ALS with behavioral impairment (ALS-bi)–like phenotypes, including deficits in sociability, and neurodegeneration. Single-nucleus transcriptomics reveal a conserved FUS-dependent gene network downregulated in these mice and ALS-ci patients. This regulon is enriched for ALS genetic risk factors and newly implicates FBXO16 in ALS-bi. Carriers of protein-truncating FBXO16 variants display behavioral abnormalities, frontotemporal atrophy, and increased levels of dementia-linked biomarkers. These findings define a neuron-intrinsic mechanism for cognitive and behavioral dysfunction in ALS and nominate FUS mislocalization and its downstream gene network as therapeutic targets. Graphical abstract Highlights Transcriptional fingerprint of FUS mislocalization is observed in cortical projection neurons of ALS patients FUS mislocalization leads to downregulation in cortical projection neurons of a cross-species conserved regulon shared with TDP43 FUS mislocalization in adult cortical projection neurons is sufficient to trigger ALS related cognitive and behavioral impairment in mouse models FUS is mislocalized and the FUS regulon is downregulated in ALS patients with cognitive impairment The FUS regulon is enriched in genetic risk factors for cognitive and behavioral impairment in ALS Carriers of protein truncating variants of FBXO16 , one of the FUS regulon genes, display behavioral, imaging and biochemical markers of ALS with behavioral impairment. |
| Document Type: |
report |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/40585174; MEDRXIV: 2025.06.16.25329673; PUBMED: 40585174; PUBMEDCENTRAL: PMC12204245 |
| DOI: |
10.1101/2025.06.16.25329673 |
| Availability: |
https://inserm.hal.science/inserm-05509094; https://inserm.hal.science/inserm-05509094v1/document; https://inserm.hal.science/inserm-05509094v1/file/nihpp-2025.06.16.25329673v1.pdf; https://doi.org/10.1101/2025.06.16.25329673 |
| Rights: |
https://creativecommons.org/licenses/by-nc-nd/4.0/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.DB98341D |
| Database: |
BASE |