Neurodegenerative Diseases Caused by Repetitive Traumatic Brain Injury Result from Accumulation of TDP-43 Via Intracellular Transport Mechanism Dysfunction

In June, a research team from the University of Pittsburgh, led by senior author Udai B. Pandey, PhD, from the Division of Child Neurology at UPMC Children's Hospital of Pittsburgh, published a new study in the journal eLife that describes a mechanistic link between repetitive traumatic brain injury and neurodegenerative disorders.

The study, conducted in collaboration with researchers from the University of Arizona, Boston University School of Medicine, and the University of Colorado, uncovered that dysfunction in nucleocytoplasmic transport (NCT) occurs in traumatic brain injury, and this dysfunction in the movement of cellular constituents into and out of the nucleus of the cell leads to accumulation of the TAR DNA binding protein 43 (TDP-43). TDP-43, through prior research, has, among other mechanisms, been implicated in neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).

Dr. Pandey and colleagues’ research, conducted in both Drosophila and rat models of repetitive TBI, also found that the nuclear pore complex (NPC) protein was upregulated in the setting of TBI, leading to protein irregularities and TDP-43 accumulation. Upregulation of the NPC protein was only one aspect of the nearly 400 different proteins that the team found to undergo significant changes in the setting of traumatic injury. Components of the NPC, a group of proteins called nucleoporins (NUP) were shown to exist in higher levels in the models after TBI.

The lead author Eric N. Anderson, PhD, a postdoctoral associate in the Pandey Laboratory, investigating human brain tissues of deceased chronic traumatic encephalopathy (CTE) patients, found both increased levels of NUP, and specifically NUP62, at increasing levels based on the severity of the disease at the time of death, while in healthy tissue comparisons, no increased levels of NUP62 were seen. Similar findings also were seen in their rat TBI models showing increasing levels of NUP62 based on disease severity.

The mechanisms that Dr. Pandey’s team uncovered linking traumatic brain injury to neurodegenerative conditions through nuclear transport dysfunction may open up a potential new approach for therapeutic targets that could repair or blunt the downstream effects seen after TBI that lead to the increases in NUP62 and TDP-43.

Reference

Anderson EN, Morera AA, Kour S, Cherry JD, Ramesh N, Gleixner A, Schwartz JC, Ebmeier C, Old W, Donnelly CJ, Cheng JP, Kline AE, Kofler J, Stein TD, Pandey UB. Traumatic Injury Compromises Nucleocytoplasmic Transport and Leads to TDP-43 Pathology. eLife. 2021; 10: e67587.