Scientists from‘Institute for Glycomics and Disarm Therapeutics of Griffith University found that in the molecule SARM1 there could be the key to better performing therapies in the treatment of neurodegenerative diseases as the Parkinson’s disease and the myotrophic lateral sclerosis (SLA).
The research highlighted the structural processes behind the activation and inhibition of SARM1: “As a trigger for nerve fiber degeneration, understanding how the SARM1 enzyme works can help us treat various neurodegenerative conditions “said Dr. Thomas Ve ofInstitute for Glycomics.
“In this study we show the molecular interactions that can activate and deactivate SARM1. This offers us a clear path for the design of new drug therapies“, Continued the scientist.
The results of the Research have been published in the scientific journal Molecular Cell.
How to act on the SARM1 molecule to effectively treat neurodegenerative diseases
In the case of neurodegenerative diseases such as peripheral neuropathythe Parkinson’s diseasethe myotrophic lateral sclerosis (ALS), the traumatic brain injuries and the glaucomawhen the nerve fibers are damaged, the SARM1 molecule is activated: “This triggers a cascade of molecular processes that leads to the self-destruction of the axon of the nerve cell, the cable that carries the electrical impulse from the body of the nerve cell to the next.“Explained Dr Ve.
“Several times thinner than a hair, but up to one meter in length for those that extend from the brain to the spinal cord, their destruction can lead to catastrophic dysfunction.“, Specified Dr. Ve.
Co-author Dr. Yun Shi stated that the SARM1 protein acts as a sensor that responds to the environment: “It turns on when the levels of a small activator molecule, the nicotinamide mononucleotide (NMN), it binds to the larger SARM1 protein like a key in a lock, opening the door to the process that leads to the breakdown of nerve fibers ”.
Once unlocked, the SARM1 molecule is capable of breaking down another key molecule called nicotinamide adenine dinucleotide (NAD+). It is a cellular fuel that nerve fibers need to function and stay alive.
Scientists used NMR spectroscopy to demonstrate how SARM1 consumes NAD + and, above all, reveal the molecular details involved in blocking this process: “We introduced a chemical developed by our industrial partner Disarm Therapeutics and demonstrated that it reacts with the NAD molecule + and binds tightly to SARM1 to prevent further breakdown of NAD +“.
The research also included the use of structural biology tools such as cryo-electron microscopy and X-ray crystallography, to determine for the first time a structure of SARM1 in complex with an inhibitor and to reveal the structural changes involved in opening the lock. which activates the molecule.
“Moving forward, the goal is to build on these findings, to create improved molecules to deactivate this pathway which is more specific to SARM1. If this can be achieved, it can ultimately lead to new treatments for patients suffering from a variety of neurological conditions “, continued the scientist.
Professor Mark von ItzsteinDirector of the Institute for Glycomics, endorsed this extraordinary discovery, identified thanks to the efforts of scientists: “New strategies for solving neurodegenerative diseases have become increasingly important due to the enormous impact on the quality of life of those suffering from these conditions ”.
Neurodegenerative diseases affect millions of individuals around the world. Alzheimer’s disease and Parkinson’s disease are among the most common neurodegenerative diseases.
Neurodegenerative diseases occur when nerve cells in the brain or peripheral nervous system lose their function over time and eventually die. Although the therapies available to date may help alleviate some of the associated physical or mental symptoms, there is currently no way to slow the progression of the disease and no cure is known.
The risk of suffering from a neurodegenerative disease is directly proportional to age. The longer you run the risk of contracting a neurodegenerative disease. The western population is aging and for this reason the scientific community is looking for a definitive solution to cure neurodegenerative diseases and develop new approaches for treatment and prevention.
Griffith’s team of scientists worked in collaboration with the team of Professor Bostjan Kobe of the University of Queensland and the group of Professors Aaron DiAntonio and Jeffrey Milbrandt of Washington University, St Louis, USA.
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