Enzyme blocker could open new treatments for neurodegenerative diseases
Researchers have uncovered how a certain molecular pathway triggers the breakdown of nerve fibers in neurodegenerative diseases – and more importantly, how to potentially switch it off. The find could lead to a new class of drugs that slows the progression of these debilitating disorders.
The focus of the study was an enzyme called SARM1, which is expressed in neurons and plays a role as an immune regulator. However, it also functions as a sensor of metabolic stress, and at a certain point it sparks a cascade of processes that eventually begins to break down axons, leading to some of the issues associated with Parkinson’s disease, ALS, neuropathy, and other neurodegenerative diseases.
But exactly what is going on during that process has remained murky, so the researchers on the new study investigated closer using nuclear magnetic resonance (NMR) spectroscopy, cryo-electron microscopy and X-ray crystallography.
The team found that a small activator molecule called NMN kicks off the process. As levels of NMN increase, it binds to SARM1 in a way that the researchers describe as a key in a lock, and once “unlocked” SARM1 begins breaking down a molecule called NAD+. Since axons need NAD+ to function, reducing its levels can eventually result in the symptoms of neurodegenerative diseases.
With the mechanism clearer, the researchers next demonstrated that a molecule that inhibits SARM1 can prevent NAD+ from breaking down. This could open a new path for developing drugs that can one day slow the progression of neurodegenerative diseases, or even prevent them.
“As a trigger for nerve fiber degeneration, understanding how the enzyme SARM1 works may help us treat several neurodegenerative conditions,” said Dr Thomas Ve, corresponding author of the study. “In this study we show the molecular interactions that can switch SARM1 on and off. This gives us a clear avenue for the design of new drug therapeutics.”
The team says that future work will investigate how to improve these SARM1-inhibiting molecules.
The research was published in the journal Molecular Cell.
Source: Griffith University