Researchers at the National Center for Advancing Translational Sciences (NCATS), Mount Sinai’s Icahn School of Medicine, and other organisations have successfully reversed the effects of several lethal inherited neurodegenerative diseases known as lysosomal storage disorders (LSDs) in patient cells and mice.
The group at NCATS, a division of the National Institutes of Health, led by translational scientist Juan Marugan, PhD, and Mount Sinai’s Yiannis Ioannou, PhD, restored the proper operation of the mitochondria and lysosomes by using novel compounds they discovered that increased the activity of TRAP1. This protein aids in the normal operation of the mitochondria, which generate energy within cells. The study’s results were released in the iScience publication.
At Mount Sinai’s Icahn School of Medicine, Dr. Ioannou teaches genetics and genomic sciences.
Genetic flaws in LSDs prohibit the cell’s lysosomes from digesting and recycling fats, carbohydrates, and proteins. As a result, these substances build up in various organs, such as the liver and brain. This may result in the mitochondria malfunctioning, further harming these organs.
To combat lysosomal storage disorders, researchers have long searched for medications that could have an influence on the lysosomes. This is a novel method of treating various illnesses. Increasing TRAP1 activity aided in the appropriate balance of the cell and improved mitochondrial protein folding. These novel compounds inhibit storage in lysosomal storage disorders by activating TRAP1 in the mitochondria.
The studies show that mitochondrial TRAP1 is a potentially new therapeutic target for a variety of central nervous system illnesses. In order to restore the internal equilibrium of the cell, the researchers found that TRAP1-initiated a “crosstalk” between mitochondria and lysosomes. The researchers found it interesting that in lysosomal storage disorders, activating TRAP1 triggers a cascade that results in the restoration of regular lysosomal function. Each lysosomal disease’s underlying genetic flaw is still present, but this interaction gets around it.
The researchers demonstrated that treating cells from individuals with Niemann-Pick disease type C1, a form of LSD, with an increase in TRAP1 activity might resolve the lipid storage problem and return cholesterol levels to normal.
Additionally, improving TRAP1 activity reversed the lipid accumulation in patient cells from different LSDs such Fabry, Farber, and Wolman illnesses. The uncommon genetic condition Niemann-Pick disease type C1 impairs the body’s capacity to digest fat in cells.
The findings, according to the researchers, may have ramifications for other neurodegenerative illnesses with comparable underlying causes, such Parkinson’s, amyotrophic lateral sclerosis, and Alzheimer’s.
Dr. Ioannou and his associates created a technique to gauge a substance’s impact on Niemann-Pick type C1. They worked together with Dr. Marugan and NCATS scientists who quickly sorted through hundreds of chemicals using the test and NCATS’ high-throughput screening capabilities.
They observed that substances that triggered TRAP1 restored appropriate mitochondrial function and began the recycling of lysosomes, aiding in the reduction of lipids in lysosomes and cells. The best-performing compounds were refined chemically and put through additional testing by the researchers.
In order to create possible pharmacological therapies, the scientists are interested in learning more about how the chemicals might reverse the symptoms of the lysosomal storage disorders. Additionally, they intend to keep developing these substances and studying their results in numerous models, including how well they can treat more prevalent neurological conditions like Alzheimer’s and Parkinson’s illnesses.