TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD
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- 0.298 · how far apart the two teachers sit on this one work
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score_only:v0-immature-baseline· verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it
Abstract
The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins and transport factors, and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts and induced pluripotent stem cell–derived neurons. Nuclear pore pathology is present in brain tissue in cases of sporadic ALS and those involving genetic mutations in TARDBP and C9orf72. Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD. Pathological TDP-43 protein aggregates are a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 pathology alters the morphology of nuclear pore complexes and cause deficits in nucleocytoplasmic transport.
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The record
- Venue
- Nature Neuroscience
- Topic
- Amyotrophic Lateral Sclerosis Research
- Field
- Medicine
- Canadian institutions
- —
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institute of Child Health and Human DevelopmentNational Institute of Neurological Disorders and StrokeNational Institute of General Medical SciencesNational Institutes of HealthUniversité Paris DiderotMcGill UniversityEmory UniversityWeston Brain InstituteAlzheimer's Drug Discovery FoundationMuscular Dystrophy AssociationALS AssociationCentre National de la Recherche ScientifiqueEuropean Molecular Biology LaboratoryNational Institute on AgingAlzheimer's AssociationMichael J. Fox Foundation for Parkinson's Research
- Keywords
- C9orf72Nuclear poreAmyotrophic lateral sclerosisTARDBPFrontotemporal dementiaNucleoporinCell biologyNuclear transportBiologyInduced pluripotent stem cellRanProtein aggregationNuclear proteinInteractomeNeurodegenerationCytoplasmNeuroscienceCell nucleusMutantPathologyGeneticsSOD1DiseaseGeneDementiaMedicineTranscription factor
- Has abstract in OpenAlex
- yes