Enzyme blocker could open new treatments for neurodegenerative diseases

Enzyme blocker could open new ...
A molecular model of the structure of SARM1 and its inhibitor
A molecular model of the structure of SARM1 and its inhibitor
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A molecular model of the structure of SARM1 and its inhibitor
A molecular model of the structure of SARM1 and its inhibitor

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

Nice article Michael. But this article leaves out the medical necessity for SARM1, and not being an embryologist studying natural neurodegeneration what follows is conjecture - the fetus grows many times more nerves in development stage than required and at some point a lack of the necessary stimuli (think retinal cells connected to the optic nerve buds in place), only the connected and firing nerves continue to develop and redundant low firing tissues degenerate. Whether or not SARM1 is part of the embryonic process is beyond my knowledge, but the question of what happens if we mute this enzyme - will we set ourselves up for neuromalignant disorders of nerves growing out of control? It sounds like science fiction, but three years ago a world wide endemic SARS-CoV2 pandemic or endemic reality seemed similar! Thanks for the good article.
Would this be useful for MND patients?