The TDP-43 protein, also known as TAR DNA-binding protein 43, is best known for its important roles in gene expression and neural plasticity in the brain.
In recent years, many studies have revealed a close relationship between TDP-43 and a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTLD) and late-life TDP-43 encephalopathy.
Breakthrough research
A team of researchers from the University of California, San Francisco used genetically engineered mice without TDP-43 in the endothelial cells, the cells that make up the walls of blood vessels.
Significant discoveries
The study revealed that these mice suffered from a variety of significant defects in the blood vessels in the brain, including:
- Hypovascularization: A significant decrease in the density of blood vessels, which prevents the supply of essential blood and oxygen to the brain tissues.
- Damage to the sprouting of new blood vessels: Difficulty in creating new blood vessel networks, which are essential for the growth and maintenance of brain tissue.
- Increased permeability of the blood-brain barrier: Penetration of unwanted cells and molecules into the brain, which can cause inflammation and nerve damage.
- Vascular degeneration: Damage to blood vessel function, which causes a decrease in blood flow and oxygen to the brain.
Far-reaching consequences
These defects in blood vessels were found to be closely related to an inflammatory response in the brain.
Microglial cells and astrocytes, the cells of the brain's immune system, were overactivated, which could lead to the destruction of nerve cells and cognitive impairment.
Innovative mechanism of action
Researchers investigated the molecular mechanism through which TDP-43 affects blood vessel function.
They discovered that a lack of TDP-43 damaged the structure and strength of the extracellular matrix, a network of proteins and sugars that surrounds and supports blood vessels.
In addition, it was found that TDP-43 is essential for the normal functioning of the β-catenin signaling pathway, which is involved in regulating the growth and development of blood vessels.
The connection to DNA
In addition to its roles in gene expression and neural plasticity, TDP-43 has also been found to be associated with the regulation of genome stability.
Studies have shown that TDP-43 binds to DNA in specific areas, where it affects gene expression and DNA damage repair.
Damaging these functions may contribute to the development of degenerative diseases.
Future Implications and New Hope
The findings of this groundbreaking study highlight the importance of TDP-43 for brain vascular health. Damage to TDP-43 can lead to accelerated aging of the brain, cognitive decline and neurodegenerative diseases.
Other functions of TDP-43:
- Regulation of processes in the nucleus: Studies have found that TDP-43 is involved in the regulation of many processes in the cell nucleus, including:
- RNA processing
- RNA export from the nucleus
- translation of RNA into protein
- Regulation of RNA splicing: TDP-43 has been found to regulate splicing of messenger RNA (mRNA), a crucial process for determining which proteins will be translated from the mRNA.
- Effect on gene activity: Studies have shown that TDP-43 can affect gene activity by binding to control regions in the genome.
Research Implications:
The findings of this groundbreaking study open a window to a new world of research and development in the field of treating degenerative diseases. Many researchers around the world continue to investigate the roles of TDP-43 and the role of blood vessels in the development of these diseases. We anticipate that in the coming years we will see significant progress in the development of new and more effective treatments:
- Drug development: The development of drugs targeting TDP-43 may lead to improving the function of blood vessels in the brain, preventing the development of degenerative diseases and even improving the condition of patients who already suffer from these diseases.
- Gene therapy: Gene therapy approaches may correct the genetic defect that causes TDP-43 deficiency or replace the defective protein.
- Treatments targeting the immune system: These treatments may focus on reducing inflammation in the brain, which contributes to the destruction of nerve cells.
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References:
https://pubmed.ncbi.nlm.nih.gov/38300714/
