Blocks nerve loss in neurodegenerative diseases

Two new studies from the Washington University School of Medicine in St.
Louis support the development of a broadly applicable treatment for neurodegenerative diseases that targets a molecule that acts as
a central executioner during the death of axons in the nervous system's circuits.

Blocking this molecular executioner prevents axon loss, which has been linked to many neurodegenerative diseases, from peripheral nerve disease to Parkinson's disease, from glaucoma to amyotrophic lateral sclerosis (ALS).

Both new studies, published Oct.
26 in the journal Science of America in the journal Clinical Investigation, reveal startling details
of how the molecule, known as SARM1, triggers axonal death at the base of the development of neurodegenerative diseases.
The study also points to new treatments
for diseases characterized by axon loss.

"We urgently need treatments for neurodegenerative diseases," said
Jeffrey Milbrandt, M.
D.
, co-senior author of the study, Professor James S.
MacDonald and chair of the Department of Genetics.
"With evidence of SARM1's central role in these diseases, we are very interested in finding ways to block this molecule – whether with small molecule inhibitors or gene therapy techniques
.
" Our latest research shows that we can also interfere with its ability to
drive destructive neuroinflammation.
We hope that this work will lead to effective new therapies
for a range of neurodegenerative and neuroinflammatory diseases.
" ”

In 2017, Milbrandt and co-senior author Aaron DiAntonio, MD, the Alan A.
and Edith L.
Wolff Professor of Developmental Biology, found that SARM1 is an enzyme
that can promote neurodegeneration.
Soon after, they co-founded a startup called nail treatment (nail treatment) to promote the development of drug compounds that inhibit SARM1 to treat axonal-mutant diseases
.
In 2020, Disarmament Therapeutics was acquired by Eli Lilly to further develop SARM1-targeted therapies
for neurodegenerative diseases.

In healthy neurons, SARM1 is always off
.
But after injury or illness, SARM1 becomes active
.
The activated SARM1 is an arsonist — it burns so much cellular energy that axons can't survive
.
This energy crisis triggers axonal disintegration
.

To further understand SARM1's role in triggering axon destruction, the researchers studied a mysterious and extremely rare progressive neuropathy syndrome — so rare that it doesn't even have
a name.
This rare disease proved to be a good model for understanding the role of
the immune system in neuroinflammatory conditions.
After sequencing the patient's genome, the researchers found that axon loss was caused by a genetic error in the gene NMNAT2, whose normal function keeps SARM1 turned off
.
As a result of these genetic errors, SARM1 is constantly activated, triggering axon destruction
.
The researchers used CRISPR gene-editing technology to reproduce these mutations
in mice.
Like people with the syndrome, these mice survived to adulthood, but motor dysfunction worsened, peripheral axons were missing and, importantly, infiltrated
by immune cells called macrophages.

The researchers were surprised to find that reducing the number of macrophages reversed axon loss and disease symptoms
in mice.
The study shows that SARM1 not only directly causes axon loss, but also plays a role in driving neuroinflammation, which only exacerbates the problem
.
The findings also suggest that some neurodegenerative diseases can be treated with immunomodulatory drugs
that block macrophages or other inflammatory immune cells.

In the second paper, the researchers investigated the possible role
of SARM1 in Charcot-Marie-Tooth disease type 2a.
Charcot-Marie-Tooth disease is a common inherited peripheral neuropathy and a good model
for studying axon loss in general.
Patients with this disorder gradually lose motor and sensory axons, and experience difficulty walking, muscle weakness, and tingling or burning sensations
in the hands and feet.
The disease is caused by mutations in an important protein in the mitochondria, which are the energy factories of
cells.
This mutation occurs in a protein called mitofusin2, which impairs the normal function
of mitochondria.
Much research has focused on abnormal mitochondria, arguing that they must be the root cause of
the disease.

Surprisingly, the researchers found that removing SARM1 in a rodent model with fibula type 2a Marie-tooth disease prevented most of the problems the animals exhibited — independent of diseased mitochondria
.
Eliminates SARM1 blocking or delaying axon death, muscle wasting, mitochondrial abnormalities, and neuromuscular connectivity (neuron-muscle interface) problems
.
Even in the presence of a mutated mitofusin2 protein, deleting SARM1 protects mitochondria from further degeneration and dysfunction
.

"When we blocked SARM1, we not only protected the axons, we also got healthier mitochondria," DiAntonio said
.
"It was a complete surprise, but we hope it can be associated with many neurodegenerative diseases centered on mitochondrial damage, such as Parkinson's disease, because many neurodegenerative diseases have a mitochondrial dysfunction component
.
"