Traumatic brain injury (TBI) is a predisposing factor for many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), chronic traumatic encephalopathy (CTE), and Alzheimer’s disease (AD). Although defects in nucleocytoplasmic transport (NCT) are reported in ALS and other neurodegenerative diseases, whether defects in NCT occur in TBI remains unknown.
We developed a TBI fly model that recapitulates many features of ALS. We performed proteomic analysis on flies exposed to repeated TBI and identified resultant alterations in several novel molecular pathways. We report that TBI upregulated nuclear pore complex (NPC) proteins and disrupted nucleocytoplasmic transport (NCT). Traumatic injury disrupted NPC protein distribution in Drosophila and a control cortical impact rat model and led to the coaggregation of NPC components and TDP-43. Furthermore, genetic upregulation of nucleoporins in vivo and cell culture triggered TDP-43 cytoplasmic mislocalization, aggregation, altered solubility, and reduced motor function and lifespan of animals. Importantly, NUP62 pathology and elevated NUP62 concentrations were found in postmortem brain tissues from patients with mild or severe CTE as well as co-aggregation of NUP62 and TDP-43. We are currently investigating the mechanism/s that trigger the changes in NPC proteins and their impact on TDP-43 proteinopathy in multiple models of TBI.