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Scientists identify mechanism linking traumatic brain injury to neurodegenerative disease

Study reveals that brain injuries can cause intracellular transport defects that can potentially lead to protein build-up and neurodegenerative disease

2021-06-01
(Press-News.org) Scientists have revealed a potential mechanism for how traumatic brain injury leads to neurodegenerative diseases, according to a study in fruit flies, and rat and human brain tissue, published today in eLife.

The results could aid the development of treatments that halt the progression of cell damage after brain injury, which can otherwise lead to neurological diseases such as amyotrophic lateral sclerosis (ALS), and Alzheimer's and Parkinson's disease.

Repeated head trauma is linked to a progressive neurodegenerative syndrome called chronic traumatic encephalopathy (CTE). Postmortem tissues from patients with CTE show dysfunctional levels of a molecule called TDP-43, which is also found in ALS, Alzheimer's disease and frontotemporal dementia.

"Although TDP-43 is a known indicator of neurodegeneration, it was not clear how repeated trauma promotes the build-up of TDP-43 in the brain," explains first author Eric Anderson, Postdoctoral Research Associate at the Department of Pediatrics at the University of Pittsburgh, Pennsylvania, US. "We have shown that repetitive brain trauma in fruit flies leads to a build-up of TDP-43. In this study we measured the changes of proteins in the fruit fly brain post injury to identify the molecular pathways that cause this."

From an analysis of 2,000 proteins, the team identified 361 that significantly changed in response to injury. These included components of the nuclear pore complex (NPC) involved in nucleocytoplasmic transport - the shuttling of important cargoes between the cell nucleus and the rest of the cell.

They found that a family of molecules that make up the NPC called nucleoporins (Nups) were increased in both larval and adult flies after injury. When they looked at the distribution pattern of Nups around the edge of the nucleus in fruit fly nerve cord cells, they found it was altered after brain trauma: there were gaps in the nuclear membrane and clumps of Nups. They also found changes in a key enzyme involved in transporting molecules in and out of the nucleus in injured brains. As a result, the transport of fluorescently labelled cargo in and out of the nucleus was impaired.

Having established that brain injury impairs the transport machinery between the nucleus and the rest of the cell, the team looked at whether the build-up of Nups leads to the aggregation of TDP-43 seen in neurodegenerative diseases. They created fruit flies that produce excess Nup protein and then stained the brain cells for the fruit fly version of TDP-43, called Tbph. They found a significant increase in the number of Tbph deposits in brains that had too much Nup compared with normal brains. Moreover, these high levels of Nups were also toxic to the flies, causing decreased motor function and reducing the distance they could climb in a certain timeframe. When the level of Nups was reduced in cells after injury, this improved the flies' climbing ability and lifespan, highlighting an avenue to explore for new treatments.

Finally, the team looked at whether the increased build-up of a Nup molecule (Nup62) was also seen in human brain tissue after injury. They examined postmortem brain tissue from patients with mild and severe CTE matched to healthy tissue from people of the same age. All mild and severe patients were involved in sports, while healthier cases were not. They found that Nup62 was present in large amounts in the wrong place in patients with mild and severe disease, but not in the healthy group, and the degree of Nup62 aggregation increased with the severity of disease. They also saw similar changes in the distribution of Nup62 in a rat model of traumatic brain injury.

"Our study reveals that traumatic brain injury can disrupt nuclear transport machinery of the cells, which plays an essential role in normal cell functions such as communication," concludes senior author Udai Pandey, associate professor of pediatrics, human genetics and neurology at the University of Pittsburgh School of Medicine. "This suggests that the accumulation of neurodegenerative hallmark proteins caused by injury begins with these nuclear transport defects, and that targeting these defects could be a strategy for preventing trauma-induced neurological disorders."

INFORMATION:

Other authors of this study include: Sukhleen Kour, PhD, Nandini Ramesh, PhD, Amanda Gleixner, PhD, Christopher Donnelly, PhD, Jeffrey Cheng, Anthony Kline, PhD, and Julia Kofler, MD, from the University of Pittsburgh; Andrés Morera and Jacob Schwartz, PhD, from the University of Arizona; Jonathan Cherry, PhD, and Thor Stein, MD, PhD, from Boston University School of Medicine; and Christopher Ebmeier, PhD, and William Old, PhD, from the University of Colorado.

This work was supported by the National Institute of Neurological Disorders and Stroke, National Institutes of Health, US.

Media contacts

Emily Packer
eLife
e.packer@elifesciences.org
+44 (0)1223 855373

Anastasia Gorelova
UPMC and University of Pittsburgh Health Sciences
gorelovaa@upmc.edu
+1-412-491-9411

About eLife

eLife is a non-profit organisation created by funders and led by researchers. Our mission is to accelerate discovery by operating a platform for research communication that encourages and recognises the most responsible behaviours. We aim to publish work of the highest standards and importance in all areas of biology and medicine, including Genetics and Genomics, and Neuroscience, while exploring creative new ways to improve how research is assessed and published. eLife receives financial support and strategic guidance from the Howard Hughes Medical Institute, the Knut and Alice Wallenberg Foundation, the Max Planck Society and Wellcome. Learn more at https://elifesciences.org/about.

To read the latest Genetics and Genomics research published today in eLife, visit https://elifesciences.org/subjects/genetics-genomics.

And for the latest in Neuroscience, see https://elifesciences.org/subjects/neuroscience.

About University of Pittsburgh Health Sciences

The University of Pittsburgh Schools of the Health Sciences include the schools of Medicine, Nursing, Dental Medicine, Pharmacy, Health and Rehabilitation Sciences and the Graduate School of Public Health. The schools serve as the academic partner to the UPMC (University of Pittsburgh Medical Center). Together, their combined mission is to train tomorrow's health care specialists and biomedical scientists, engage in groundbreaking research that will advance understanding of the causes and treatments of disease and participate in the delivery of outstanding patient care. Since 1998, Pitt and its affiliated university faculty have ranked among the top 10 educational institutions in grant support from the National Institutes of Health. For additional information about the Schools of the Health Sciences, please visit http://www.health.pitt.edu.



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[Press-News.org] Scientists identify mechanism linking traumatic brain injury to neurodegenerative disease
Study reveals that brain injuries can cause intracellular transport defects that can potentially lead to protein build-up and neurodegenerative disease