Scientists at the National Center for The Advancement of Translational Science (NCATS) at the Icahn School of Medicine in Mount Sinai, New York, and other researchers have reversed the effects
of several life-threatening inherited neurodegenerative diseases— lysosomal storage disorders (LSDs) in patient cells and mice.
The research team, led by Dr.
Yannis Ioannou of Mount Sinai University and Dr.
Juan Marugan, a translational scientist at the National Institutes of Health NCATS, restored the normal function
of mitochondria and lysosomes by using new compounds they found capable of increasing TRAP1 activity.
This protein helps the energy-producing mitochondria within the cell function properly
Dr Ioannou is Professor of Genetics and Genomic Sciences at Icahn School of Medicine at
LSDs are characterized by genetic defects that prevent the lysosomes of cells from breaking down and circulating fats, sugars, and proteins, causing them to accumulate in organs, including the liver and brain
This can lead to mitochondrial malfunction, leading to further damage
to these organs.
What is this study trying to reveal? Researchers have long been looking for drugs that can affect lysosomals, trying to influence lysosomal storage diseases
This is a new way to treat these diseases
The increase in TRAP1 activity promotes mitochondrial protein folding, promoting proper balance
These first-rate molecules activate TRAP1 in mitochondria and reduce storage in lysosomal storage
Conclusion: The data suggest that mitochondrial TRAP1 is a potential new therapeutic target for a variety of diseases
affecting the central nervous system.
The researchers found that trap1 initiates a "dialogue" between mitochondria and lysosomes, which they determined is essential
for restoring balance within the cell.
Surprisingly, the researchers note that when TRAP1 is activated, a cascade is initiated, leading to the restoration
of normal lysosomal function in lysosomal storage diseases.
The defect that causes every lysosomal disease remains, but this crosstalk bypasses the genetic defect
The team showed that increasing the activity of TRAP1 in cells from patients with C1-type Niemann-Pick disease (a type of LSD) can correct lipid storage disorders and restore normal cholesterol levels
In addition, increased TRAP1 activity in cells from patients with other LSDs, such as Fabry, Farber and Wolman diseases, also corrected their respective lipid stores
(Niemann-Pick disease type C1 is a rare genetic disorder that affects the body's ability to
metabolize fat within cells.
Why is this research important? The researchers say the findings could have implications for other neurodegenerative diseases with similar underlying causes, such as Parkinson's, amyotrophic lateral sclerosis and Alzheimer's
How was this research conducted? Dr.
Ioannou and his colleagues developed a test method to measure the effect
of compounds on C1-type Niemann-Pick disease.
Working with Dr.
Marugan and scientists at NCATS, they used NCATS's high-throughput screening equipment for testing, rapidly screening thousands of compounds
They found that compounds that activate TRAP1 get the mitochondria back to function and restart the circulating capacity of the lysosomes, helping to reduce fat
in the lysosomes and cells.
The researchers chemically modified the compounds that worked best and tested
Next: Scientists hope to learn more about how these compounds reverse the characteristics of lysosomal storage disease, which will help develop potential drug treatments
They also plan to continue refining the compounds and examining their effects in a variety of models, including their ability
to influence more common neurological diseases such as Alzheimer's and Parkinson's disease.
Activating mitochondrial TRAP1 stimulates mitochondrial-lysosomal crosstalk and corrects lysosomal dysfunction