Researchers Reverse LSDs in Patient Cells and Mice

Research led by the Icahn School of Medicine at New York’s Mount Sinai has reversed the effects of several lysosomal storage disorders (LSDs) in patient cells and mice.  LSDs are life-threatening, inherited neurodegenerative diseases characterized by genetic defects that prevent the cell’s lysosomes from breaking down and recycling fats, sugars, and proteins, leading to their accumulation in organs, including the liver and brain. This build-up can cause a malfunction in the mitochondria, leading to further damage to these organs.

Led by Yiannis Ioannou, PhD, a professor of Genetics and Genomic Sciences at the Icahn School of Medicine and Juan Marugan, PhD, a translational scientist from the National Center for Advancing Translational Sciences (NCATS), the team was able to restore the proper function of both the mitochondria and lysosomes by using novel compounds that increased the activity of TRAP1, a protein that helps mitochondria function properly. 

The work involved developing a test to measure the effect of compounds on the LSD Niemann-Pick disease type C1. Marugan and NCATS scientists used the test with NCATS’ high-throughput screening facilities to rapidly sift through thousands of compounds. They found that the compounds that activated TRAP1 made the mitochondria work properly again and restarted the lysosomes’ recycling ability, helping reduce fats in the lysosomes and cells. The researchers chemically improved the compounds that appeared to work best and tested them further.

They found that TRAP1 initiated a “crosstalk” between mitochondria and lysosomes which, they determined, was essential to restoring the internal cellular balance. Surprisingly, TRAP1, when activated, initiates a cascade that leads to restoration of normal lysosomal function in LSDs. The defect causing each lysosomal disease is still present, but this crosstalk bypasses the genetic defect. The team showed that increasing the activity of TRAP1 in cells from people with Niemann-Pick disease type C1 could correct the lipid storage disorder and restore normal cholesterol levels. In addition, increasing TRAP1 activity in patient cells from other LSDs such as Fabry, Farber, and Wolman diseases also corrected their respective lipid storage.

The data also suggests that mitochondrial TRAP1 is a potential novel therapeutic target for multiple disorders that affect the central nervous system. For this reason, the findings—published recently in iScience—could have implications for other neurodegenerative diseases that have similar underlying causes, such as Parkinson’s, amyotrophic lateral sclerosis, and Alzheimer’s.

Going forward, the scientists would like to understand more about how the compounds can reverse characteristics of the LSDs, which will be instrumental in developing potential drug treatments. They also plan to continue refining these compounds and examining their effects in various models, including their ability to affect more common neurological disorders.