Lab-created protein “seed” unlocks the mystery behind devastating brain diseases

Belgian scientists have successfully created protein fragments in the laboratory that trigger the same destructive processes seen in patients with ALS and frontotemporal dementia, opening new windows for the development of these devastating neurological diseases.

The study was published yesterday in Neuron, focusing on TDP-43, a protein found throughout the human body that plays a crucial role in regulating gene expression and cellular stress response. Although generally beneficial, the protein becomes problematic when it abandons its proper place under several neurodegenerative conditions and forms harmful clumps.

“In almost all cases of ALS and about half of frontotemporal dementia, TDP-43 pathology is considered a defining feature,” explained Professor Sandrine Da Cruz, group leader at the Vib-Ku Leuven Center for Brain and Disease Research. “In the brains of these patients, TDP-43 is mislocalized in some way, accumulates in the cytoplasm, forms insoluble inclusions, and is depleted from the nucleus.”

This discovery was made in the Vlaams Institut Voor Biotechnologie (VIB) in Rudo, Belgium, an important step in understanding the disease and allows patients to move, think and operate independently. Nearly 30,000 Americans currently live with ALS, while frontotemporal dementia affects about 60,000 people in the United States alone.

For families watching loved ones, deteriorating from these conditions, this advancement offers hope in daily care challenges. As the spring arrives in Belgium, the team at Da Cruz will continue to work in the lab in detail.

Leuven’s researchers created what they call “amyloid-like fibers” (essentially tiny protein lines), created from fragments of TDP-43. When introduced into human cells, including neurons derived from induced pluripotent stem cells, these fibrils trigger the same protein adverse behavior in the patient’s brain.

Jens Rummens, a doctoral student of the study, noted that their lab aggregates closely mimic what they saw in actual patients: “Fibril-induced TDP-43 aggregates show many of the modifications we also show in the patient’s brain, including phosphorylation and flooding of the cytoplasm.”

This detail is crucial because it demonstrates two key aspects of the disease process – both proteins leave proper positions (nuclei) and form toxic clumps in the wrong positions (cytoplasm).

These findings support an increasing theory that these protein-related brain diseases spread in a “prion-like” way, in which misfolded proteins trigger normal proteins to be misstained, creating a cascade effect that spreads throughout the brain. This mechanism is also associated with other neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease.

Despite these progress, there are still many problems. Researchers still do not fully understand how TDP-43 is captured in aggregates, what these aggregates contain or how exactly lead to cell death. The role of TDP-43 mutations, aging and other factors also needs further research.

The beauty of this breakthrough lies in its practical application. The team created a lab model that can be used to investigate these issues in a controlled environment.

“We have developed a valuable model that shows two aspects of TDP-43 pathology – cytoplasmic aggregation and nuclear depletion,” Da Cruz said. “This will be a powerful asset that can help researchers around the world further uncover the disease mechanisms induced by TDP-43 and enable us to screen potential drug candidates that alter disease progression.”

As spring turns to summer, researchers will continue to use these protein seeds to cultivate our understanding of neurodegenerative diseases and potentially produce a day of treatments that could one day bring new life to patients facing these devastating diagnoses.