Researchers identify a potential pathway against

Researchers identify potential pathway against inherited neurodegenerative diseases

Image: Researchers at the Icahn School of Medicine at Mount Sinai and NCATS have identified compounds that reverse the effects of several neurodegenerative diseases called lysosomal storage disorders (LSDs) in patient cells and mice. LSDs are characterized by genetic defects that prevent the decomposition of particles in the cell and the recycling of fats, sugars and proteins, which can accumulate in the liver and brain. This can cause an imbalance in the energy-producing mitochondria. The compounds increased the activity of TRAP1, a protein that helps mitochondria function properly. Above, lipid-filled lysosomes (red) of C1-type Niemann-Pick disease cells are normalized upon mitochondrial TRAP1 activation (green).
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Credit: Yuano Lab, Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai

Main takeaway: Scientists at the Icahn School of Medicine at Mount Sinai in New York, National Center for the Advancement of Transformative Science (NCATS)and, elsewhere, reversed the effects of several life-threatening inherited neurodegenerative diseases called lysosomal storage disorders (LSDs) in patient cells and mice.

The team led by Yiannis Ioannou, PhD, and translation scientist Juan Marugan, at NCATS, part of the National Institutes of Health, restored the proper function of both mitochondria and lysosomes using new compounds they identified that increased activity. from TRAP1. This protein helps mitochondria, which produce energy within cells, to function properly. The results were recently reported in iScience.

Dr. Ioannou is Professor of Genetics and Genomics at the Icahn School of Medicine at Mount Sinai.

LSDs have genetic defects that prevent cell lysosomes from degrading and recycling lipids, sugars, and proteins, leading to their accumulation in organs, including the liver and brain. This can cause an imbalance in the mitochondria, leading to further damage to these organs.

What did the study seek to uncover? Researchers have long been searching for drugs that can affect lysosomes in an effort to influence lysosomal storage diseases. This is a new approach to these diseases. Increased TRAP1 activity enhanced mitochondrial protein folding and facilitated proper cell homeostasis. These first-in-class molecules activate TRAP1 in mitochondria and reduce storage in lysosomal storage diseases.

Study conclusions: The data demonstrate that mitochondrial TRAP1 is a potential new therapeutic target for multiple disorders affecting the central nervous system. The researchers discovered that TRAP1 triggered a “crosstalk” between mitochondria and lysosomes which, in their view, was necessary to restore internal cellular homeostasis. What is surprising, the researchers note, is that TRAP1, when activated, initiates a cascade that leads to the restoration of normal lysosomal function in lysosomal storage diseases. The defect that causes each lysosomal disease still exists, but this crosstalk goes beyond the genetic defect. The team showed that increased TRAP1 activity in cells from people with type C1 Niemann-Pick disease, a type of LSD, could correct a fat storage disorder and restore normal cholesterol levels. In addition, increased TRAP1 activity in patient cells from other LSD diseases such as Fabry, Farber, and Wollmann diseases also corrected their lipid storage. (Niemann-Pick disease type C1 is a rare genetic disorder that affects the body’s ability to metabolize fat within cells.)

Why is research important? The researchers suggest that the findings could have implications for other neurodegenerative diseases that have similar underlying causes, such as Parkinson’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease.

How was the study conducted? Dr. Ioannou and colleagues developed a test to measure the effect of the compounds on C1-type Niemann-Pick disease. They teamed up with Dr. Marujan and NCATS scientists who used the test with NCATS’s high-throughput screening facilities to rapidly screen thousands of compounds.

They discovered that the compounds that activate TRAP1 made mitochondria function properly again and recycled the ability of lysosomes, helping to reduce lipids in lysosomes and cells. The researchers chemically improved the compounds that seemed to work best and tested them further.

Next steps: Scientists would like to understand more about how the compounds can reverse the properties of lysosomal storage diseases, which will be useful in developing potential drug therapies. They also plan to continue to improve these compounds and study their effects in various models, including their ability to affect more common neurological disorders such as Alzheimer’s disease and Parkinson’s disease.

Paper title: Mitochondrial TRAP1 activation stimulates mitochondrial and lysosomal crosstalk and corrects lysosomal dysfunction.


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