Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology

• Published in: eLife Vol. 10
• Main Authors: Anderson, Eric N, Morera, Andrés A, Kour, Sukhleen, Cherry, Jonathan D, Ramesh, Nandini, Gleixner, Amanda, Schwartz, Jacob C, Ebmeier, Christopher, Old, William, Donnelly, Christopher J, Cheng, Jeffrey P, Kline, Anthony E, Kofler, Julia, Stein, Thor D, Pandey, Udai Bhan
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 01.06.2021; eLife Sciences Publications, Ltd
• Subjects: Active Transport, Cell Nucleus; Alzheimer's disease; Amyotrophic lateral sclerosis; Animals; Animals, Genetically Modified; Brain - metabolism; Brain - pathology; Brain Injuries, Traumatic - genetics; Brain Injuries, Traumatic - metabolism; Brain Injuries, Traumatic - pathology; Case-Control Studies; Chronic traumatic encephalopathy; Disease Models, Animal; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Encephalopathy; Genetics and Genomics; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Head injuries; HEK293 Cells; Humans; Insects; Lethality; Life span; Localization; Longevity; Male; Membrane Glycoproteins - metabolism; Motor Activity; Movement disorders; Mutation; Neurodegeneration; Neurodegenerative diseases; Neuroscience; Nuclear Pore - genetics; Nuclear Pore - metabolism; Nuclear Pore - pathology; Nuclear Pore Complex Proteins - metabolism; Nuclear transport; Nucleoporins; Ontology; Parkinson's disease; Pathology; Protein Aggregates; Protein Aggregation, Pathological; Protein transport; Proteins; Proteomics; Rats; Rats, Sprague-Dawley; TDP-43; TDP-43 Proteinopathies - genetics; TDP-43 Proteinopathies - metabolism; TDP-43 Proteinopathies - pathology; Trauma; Traumatic brain injury; genetics; rat; TDP-43; neuroscience; neurodegeneration; genomics; D. melanogaster; chronic traumatic encephalopathy; amyotrophic lateral sclerosis; human
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.67587

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 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.