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

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.

Neuropathology in chronic traumatic encephalopathy: a systematic review of comparative post-mortem histology literature

“…We found a strong consensus that TDP-43 pathology is elevated and widespread in CTE compared to normal aging and AD cases. All four studies reported that TDP-43 aggregation is absent in normal aged cases but present in spinal cord, hippocampus, amygdala, frontal cortex, medial temporal lobe, and/or basal ganglia of CTE cases [ 5 , 49 , 59 , 60 ]. One study showed that TDP-43 inclusions were more abundant and widespread in CTE than AD, with a distribution more closely resembling FTD with TDP-43 inclusions [ 49 ].…”

“…Proteins involved in nuclear pore complex and nucleocytoplasmic transport contribute to the regulation of protein synthesis. Disruptions to the nuclear pore complex have been reported in other neurodegenerative diseases, but only one study investigated this in CTE postmortem tissue [ 5 ]. Nuclear pore glycoprotein p62 (NUP62) is an essential component of the nuclear pore complex and immunoreactivity for NUP62 was found to be increased in CTE tissue compared to normal age-matched cases.…”

“…Nuclear pore glycoprotein p62 (NUP62) is an essential component of the nuclear pore complex and immunoreactivity for NUP62 was found to be increased in CTE tissue compared to normal age-matched cases. Increased cytoplasmic NUP62 co-labelling with phospho-TDP-43 in severe CTE cases compared to mild cases suggests alterations to the nuclear pore complex are related to protein aggregation and disease severity [ 5 ].…”

TDP-43 and Inflammation: Implications for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

“…Research using Drosophila models to investigate the link between repetitive brain trauma and ALS show that Drosophila have implicated disruptions to altered protein clearance, autophagy pathways, and nucleocytoplasmic transport [175,176]. In Drosophila expressing C9orf72, repetitive brain trauma showed increased mortality and locomotor dysfunction [175], which may be explained by TBI altering protein clearance pathways such as the ubiquitin-proteosome system or autophagy pathway.…”

“…Noteworthy, SQSTM1/p62 is an autophagy receptor and has been identified as a rare genetic variant in both ALS and FTD in addition to being able to activate the NF-κβ pathway [72]. In a further follow up study by Anderson and colleagues, proteomics analysis of Drosophila brains following repetitive trauma demonstrated that repetitive TBI upregulated nuclear pore proteins, altered nucleoporin stability, nucleocytoplasmic trans-port proteins, and nucleocytoplasmic transport itself [176]. Interestingly, this upregulation led to TDP-43 mislocalisation, aggregation, and phosphorylation in addition to decreased motor function and lifespan.…”