Researchers discover new way to treat neurological disorders in cells of patients and animals

Washington: Researchers from the National Center for Advancing Translational Sciences (NCATS), Mount Sinai’s Icahn School of Medicine and other organizations have succeeded in reversing the effects of several life-threatening inherited neurodegenerative diseases known as lysosomal storage disorders (LSD) in patient cells and mice.

The group from NCATS, a division of the National Institutes of Health, led by translational scientist Juan Marugan, PhD, and Yiannis Ioannou, PhD, of Mount Sinai, restored the proper functioning of mitochondria and lysosomes using new compounds that they found that increased the activity of TRAP1. This protein helps the proper functioning of mitochondria, which generate energy in cells.

The results of the study have been published in the publication iScience.

At the Icahn School of Medicine at Mount Sinai, Dr. Ioannou teaches genetics and genomic sciences.

Genetic defects in LSD prevent the cell’s lysosomes from digesting and recycling fats, carbohydrates and proteins. As a result, these substances accumulate in various organs, such as the liver and the brain. This can cause the mitochondria to malfunction, further damaging these organs.

To combat lysosomal storage diseases, researchers have long searched for drugs that could influence lysosomes. This is a new method of treating various diseases. The increased TRAP1 activity contributed to proper cell balance and improved mitochondrial protein folding. These novel compounds inhibit storage in lysosomal storage disorders by activating TRAP1 in mitochondria.

Studies show that mitochondrial TRAP1 is a potentially novel therapeutic target for various diseases of the central nervous system. In order to restore the internal balance of the cell, the researchers discovered that TRAP1 initiates a “crosstalk” between the mitochondria and the lysosomes. Researchers have found it interesting that activation of TRAP1 triggers a cascade that results in the restoration of regular lysosomal function in lysosomal storage diseases.

The underlying genetic defect of each lysosomal storage disease is still present, but this interaction circumvents it. The team demonstrated that treating cells from individuals with Niemann-Pick type C1 disease, a form of LSD, with an increase in TRAP1 activity could solve the problem of lipid storage and bring the level normal cholesterol. Additionally, enhancement of TRAP1 activity reversed lipid storage in cells of patients of different LSDs such as Fabry, Farber, and Wolman diseases. The rare genetic condition Niemann-Pick disease type C1 impairs the body’s ability to digest fat in cells.

The findings, the researchers say, could have ramifications for other neurodegenerative diseases with comparable underlying causes, such as Parkinson’s disease, amyotrophic lateral sclerosis and Alzheimer’s disease.

Dr. Ioannou and his associates have created a technique to assess the impact of a substance on Niemann-Pick type C1. They worked with Dr. Marugan and NCATS scientists who quickly sorted through hundreds of chemicals using the NCATS high-throughput screening test and facilities.

They found that substances that triggered TRAP1 restored proper mitochondrial function and began lysosome recycling, contributing to the reduction of lipids in lysosomes and cells. The top-performing compounds were chemically refined and subjected to additional testing by the researchers.

In order to create possible pharmacological therapies, scientists want to learn more about how chemicals can reverse the symptoms of lysosomal storage diseases. Additionally, they plan to continue to develop these substances and study their results in many models, including how well they can treat more common neurological diseases like Alzheimer’s and Parkinson’s.


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