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Brain changes can be studied in the very early stages of neurodegenerative diseases
Many changes occur in the brain long before symptoms appear. This has been shown in mice in two prion disease studies, where the brain gradually deteriorates. The results suggest that changes can be studied very early in the disease process, which is important if we want to develop treatments. The studies were conducted by researchers at Linköping University, Sweden. Prion diseases are rare, incurable diseases that cause brain deterioration. Two well-known examples are mad cow disease and scrapie in sheep. In the 1990s, people who ate meat from cattle infected with mad cow disease were...
Brain changes can be studied in the very early stages of neurodegenerative diseases
Many changes occur in the brain long before symptoms appear. This has been shown in mice in two prion disease studies, where the brain gradually deteriorates. The results suggest that changes can be studied very early in the disease process, which is important if we want to develop treatments. The studies were conducted by researchers at Linköping University, Sweden.
Prion diseases are rare, incurable diseases that cause brain deterioration. Two well-known examples are mad cow disease and scrapie in sheep. In the 1990s, people who ate meat from cattle infected with mad cow disease were affected by a variant of the disease.
Prions are remarkable creatures. These are infectious pathogens that consist exclusively of a specific protein. The normal form of the prion protein is found in all mammals, but can undergo a strange transformation and become toxic. This transformation triggers a cascade of changes that converts normal protein molecules into the toxic variant.”
Lech Kaczmarczyk, senior research engineer in the Department of Biomedical and Clinical Sciences (BKV) at Linköping University and lead author of one of the studies
Prion diseases can be transmitted to organisms through infectious prions. But they can also arise from genetic changes (mutations) in the gene that codes for the prion protein. The area of the brain affected depends on the location of the mutation in the gene. This can happen even though the normal prion protein is present in many cell types and many areas of the brain. This surprising property is known as “selective vulnerability” and can be seen in other, more common nervous system diseases (neurodegenerative diseases). For example, in people with Parkinson's disease we see damage in the parts of the brain that control body movements, while in Alzheimer's disease, degeneration of other parts of the brain causes dementia and cognitive problems.
The researchers wanted to identify the underlying causes of the selective susceptibility that causes different diseases to produce different symptoms. A major challenge for researchers is that the affected parts of the brain are already damaged when the disease manifests itself. This makes it difficult to investigate how the process began.
The researchers who conducted the current studies examined disease models of various prion diseases in mice. The researchers used new methods that allowed them to discover disease mechanisms long before symptoms appear. There are no visible changes in brain activity, no changes in the animals' behavior, and the brain tissue appears completely normal, but researchers know that the mice are destined to develop the disease and they can predict when it will occur.
"Many researchers and clinicians take the view that therapies for neurodegenerative diseases need to be applied at very early stages, even before clinical signs appear, in order to achieve benefit. Therefore, it is important to understand what happens in the earliest stages of the disease," says Walker Jackson, associate professor at BKV at Linköping University and leader of the studies.
In one of the studies, researchers examined how different cell types respond when infected with prions, while in the other they examined two genetic prion diseases: fatal familial insomnia and Creutzfeldt-Jakob disease (CJD). FFI is characterized by severe insomnia, while the main impact of CJD is dementia and impaired cognitive function. Although these two diseases show different symptoms in their later stages, researchers found similarities in the early stages, before symptoms appear.
"In our studies, we see coordinated changes in gene expression in the very early stages of the diseases, as if the cells were trying to change something in their biology to fight off the disease. Some researchers are looking at changes in gene expression patterns during the disease." "This may be a malfunction, but our results suggest that these are coordinated cellular reactions," says Walker Jackson.
In the first study, the expression patterns of so many genes were altered in the early stages of the diseases, just before symptoms appeared, that it was impossible to select a treatment target. This discovery may help explain why many drug trials failed to produce desired treatment results; They focused on a single gene or target and overlooked the other problems in the cell.
Cells continually produce new proteins depending on which genes are active. They are produced in organelles of the cell known as “ribosomes.” For both studies, the researchers used a method that allowed them to track the ribosomes in a specific cell type, giving them an idea of what was happening in the cell at that particular moment.
In their second study, they examined six cell types of the two genetic prion diseases, which are caused by different mutations in the prion gene.
"We were surprised to find that the same cell type responds most strongly in both diseases and that the cells respond in essentially the same way. So even though the two diseases are very different in their later stages, there may be underlying causes." Similarities that represent interesting targets for treatment in the long term,” says Susanne Bauer, doctoral student at BKV and lead author of the second study, published in the Life Science Alliance.
The cell type in question is a nerve cell that expresses somatostatin and has not previously been studied in detail in prion disease research. However, previous studies suggest that this cell type may be affected in the early stages of other neurodegenerative diseases.
The researchers also found that the cellular changes in the early stages of disease in genetic prion diseases were completely different than in infectious prion diseases. This shows that there are major molecular differences between prion diseases of different origins, even if the same prion protein is fundamentally defective. The researchers are now continuing their studies and will use the same methods to investigate other, more common neurodegenerative diseases.
This work was supported by the Knut and Alice Wallenberg Foundation and the German 850 Center for Neurodegenerative Diseases (DZNE).
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References:
Article 1: Distinct translatome changes in specific neuronal populations precede electroencephalographic changes in prion-infected mice Lech Kaczmarczyk, Melvin Schleif, Lars Dittrich et al., (2022), PLoS Pathology, published online on August 12, 2022, doi: 10.1371/journal.ppat.1010747
Article 2: Translational profiling of neuronal subtypes in model mice with fatal familial insomnia reveals TOR signaling in somatostatin neurons Susanne Bauer, Lars Dittrich, Lech Kaczmarczyk et al., (2022), Life Science Alliance, published online on October 3, 2022, doi: 10.26508/lsa.202201530
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