2023-06-05 14:40:43
Medicine
EPFL discovers a mechanism responsible for neurological diseases
Scientists have understood how proteins aggregate and damage the brain, opening up treatment prospects for Alzheimer’s, Parkinson’s and Charcot’s disease.
Published
Neurodegenerative diseases are caused by aggregates that form in several parts of the brain.
Getty Images/iStockphoto
Several neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and Charcot’s disease (also called ALS, amyotrophic lateral sclerosis) are caused by proteins that go astray before aggregating into fibrils accumulating in specific brain areas. The highly unstable protein called TDP-43 is suspected to be the main culprit.
Aggregation of the TDP-43 protein is indeed a main feature of ALS and other neurodegenerative diseases. Once formed, these aggregates can spread to different brain areas where they alter normal and functional TDP-43. But what triggers TDP-43 aggregation? What are the mechanisms responsible for the release of its pathogenic effects? This lack of knowledge prevents the development of effective drugs to block this aggregation or neutralize its toxic properties.
Enzymes make the protein vulnerable
In an EPFL study, published in the journal “Nature Neuroscience» and carried out in collaboration with scientists from the University of Pennsylvania, Senthil T. Kumar and Hilal Lashuel discovered a new mechanism responsible for the release of the pathogenic effects of the aggregate of TDP-43, prepared in a test tube or isolated from the brains of patients after death. The surfaces of these aggregates must first be cleaved (split) by enzymes to reveal hidden sticky surfaces that attract normal TDP-43 proteins and cause new aggregates to form.
Using cryo-electron microscopy, the scientists showed that the filaments of TDP-43 are buried inside a larger filament and are inaccessible, that is, they are not yet pathological, because they are covered by the globular parts of the protein. As long as these filaments are buried, they are invisible and cannot be accessed by other molecules or proteins. Simply put, TDP-43 becomes pathological when its outer coating is split open to reveal its “sticky” inner filaments, but remains invisible when its outer coating is intact.
In the foreground, TDP-43 fibrils comprising a full-length protein are digested by the enzyme proteinase K (left to right), thinning the fibril exposing the nucleus. In the background, the cell model shows fibril seeding only when the nucleus is exposed (on the right, the bright blobs), whereas when the fibril nucleus is obscured, on the left, there is no d seeding aggregates into the cells, so we can only see the diffuse staining. This shows that the nucleus must be unmasked to render the fibrils toxic and capable of seeding.
EPFL/Galina Limorenko.
A therapy to slow down the disease
“Our results show that inhibiting the enzymes responsible for TDP-43 filament cleavage represents a viable therapeutic strategy to slow the formation of TDP-43 aggregates and prevent their spread in the brain, thereby halting disease progression. As a second step, we plan to identify these enzymes and determine whether inhibiting their activity could prevent TDP-43 aggregation and neurodegeneration in cellular and animal models of ALS”, explains Hilal Lashuel, professor at EPFL and head of the laboratory that conducted the study.
These recent findings also have implications for the development of new tools and methods for the early diagnosis of ALS and other neurodegenerative diseases. The protective globular layer may explain why TDP-43 fibrils are so difficult to detect. Often, standard methods and dyes commonly used to detect and monitor fibril formation by other suspicious proteins in the brain failed to detect TDP-43 fibrils. “It also explains why it has been very difficult to develop imaging agents using intact TDP-43 fibrils. These imaging agents are essential for enabling early diagnosis, monitoring disease progression and evaluating the effectiveness of new therapies,” continues Senthil T. Kumar, lead author of the article.
Reproduce the pathology in a test tube
The scientists showed that they could produce TDP-43 fibrils with the same central sequence as fibrils from patients’ brains. “But we still have to determine if the unmasked fibril core has the same structure,” says Hilal Lashuel. If we can do this, then we will have the only system to produce the actual pathology in the test tube. This will have important implications for understanding the influence of disease-related mutations and protein modifications on TDP-43 aggregation and will facilitate the development of new drugs that block this aggregation, neutralize its pathogenicity or bind to the aggregates. of TDP-43 and facilitate their detection in the brain”.
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