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Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology
- Source :
- eLife, Vol 10 (2021), eLife
- Publication Year :
- 2021
- Publisher :
- eLife Sciences Publications Ltd, 2021.
-
Abstract
- Traumatic brain injury (TBI) is a predisposing factor for many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and chronic traumatic encephalopathy (CTE). Although defects in nucleocytoplasmic transport (NCT) is reported ALS and other neurodegenerative diseases, whether defects in NCT occur in TBI remains unknown. We performed proteomic analysis on Drosophila exposed to repeated TBI and identified resultant alterations in several novel molecular pathways. TBI upregulated nuclear pore complex (NPC) and nucleocytoplasmic transport (NCT) proteins as well as alter nucleoporin stability. Traumatic injury disrupted RanGAP1 and NPC protein distribution in flies and a rat model and led to coaggregation of NPC components and TDP-43. In addition, trauma-mediated NCT defects and lethality are rescued by nuclear export inhibitors. Importantly, genetic upregulation of nucleoporins in vivo and in vitro triggered TDP-43 cytoplasmic mislocalization, aggregation, and altered solubility and reduced motor function and lifespan of animals. We also found NUP62 pathology and elevated NUP62 concentrations in postmortem brain tissues of patients with mild or severe CTE as well as co-localization of NUP62 and TDP-43 in CTE. These findings indicate that TBI leads to NCT defects, which potentially mediate the TDP-43 pathology in CTE.
- Subjects :
- Male
Pathology
amyotrophic lateral sclerosis
TDP-43
Animals, Genetically Modified
Rats, Sprague-Dawley
Brain Injuries, Traumatic
Drosophila Proteins
chronic traumatic encephalopathy
Nuclear pore
Amyotrophic lateral sclerosis
Biology (General)
Membrane Glycoproteins
D. melanogaster
General Neuroscience
Neurodegeneration
GTPase-Activating Proteins
neurodegeneration
Brain
General Medicine
DNA-Binding Proteins
Traumatic injury
Drosophila melanogaster
Medicine
Nucleoporin
Research Article
Human
medicine.medical_specialty
Traumatic brain injury
QH301-705.5
Science
Longevity
Active Transport, Cell Nucleus
Motor Activity
Protein Aggregation, Pathological
General Biochemistry, Genetics and Molecular Biology
Protein Aggregates
medicine
Animals
Humans
General Immunology and Microbiology
business.industry
Genetics and Genomics
medicine.disease
nervous system diseases
Nuclear Pore Complex Proteins
Chronic traumatic encephalopathy
Disease Models, Animal
HEK293 Cells
Nucleocytoplasmic Transport
Case-Control Studies
TDP-43 Proteinopathies
Nuclear Pore
Rat
business
Neuroscience
Subjects
Details
- Language :
- English
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- eLife
- Accession number :
- edsair.doi.dedup.....8fd5c7d325b1e29d708aa4ced21b26fe