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.
Highlights
Traumatic brain injury (TBI) is one of the most common causes of death and disability worldwide (Zaninotto et al, 2018)
Complex network analysis based on gene ontology (GO) association analysis in BiNGO (Cytoscape 3) of the TBI-associated brain proteome compared to non-TBI controls identified distinct categories of altered proteins, with the majority upregulated (Figure 1B and C; Figure 1—figure supplement 1A-E; Supplementary files 1 and 3)
TBI causes nuclear dysfunction (Tajiri et al, 2016), it has remained unknown whether TBI leads to nucleocytoplasmic transport (NCT) defects that might be linked to TDP-43 pathology in chronic traumatic encephalopathy (CTE)
Summary
Traumatic brain injury (TBI) is one of the most common causes of death and disability worldwide (Zaninotto et al, 2018). Multiple mechanisms have been proposed to explain abnormal cytoplasmic accumulation of TDP-43 and progressive spreading of TDP-43 pathology in the context of neurodegenerative diseases. Alteration in RBPs such as TDP-43 could be an important indicator of neurodegeneration These mechanisms potentially explain the role of pathological mutations of TDP-43 in the context of neurodegenerative disease, how TDP-43 aggregates form and lead to neurodegeneration in the absence of mutations, such as in the brains of repeated trauma patients, is unclear. We performed proteomic analysis on Drosophila brains to identify the molecular pathways that were altered in response to traumatic injury In this manuscript, we found that repeated trauma upregulates nuclear pore proteins, alter nucleoporin stability, and NCT proteins as well as alters RanGAP1 and nucleoporins distribution, and NCT in vivo. Our findings of NUP62 pathology and increased NUP62 concentrations in brain tissues from patients with CTE suggest that NCT defects are linked with traumatic injury, which potentially mediates TDP-43 pathology
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