Novel Strategy Shows Potential to Stop the Progression of Neurodegenerative Diseases

Degenerative nerve diseases affect many of your body’s activities, such as balance, movement, talking, breathing, and heart function. Many of these diseases are genetic. Sometimes the cause is a medical condition such as alcoholism, a tumor, or a stroke. Other causes may include toxins, chemicals, and viruses. 

Degenerative nerve diseases can be serious or life-threatening. It depends on the type. Most of them have no cure. Treatments may help improve symptoms, relieve pain, and increase mobility.

In healthy neurons, SARM1 is always switched off. But after injury or due to disease, SARM1 becomes active. Activated SARM1 is an arsonist — burning so much cellular energy that the axons can’t survive. This energy crisis triggers axons to disintegrate. To understand more about SARM1’s role in triggering axon destruction, the researchers studied a mysterious and extremely rare progressive neuropathy syndrome , so rare, it lacks a name. This rare disease turned out to be a good model for understanding the role of the immune system in neuroinflammatory conditions generally. Sequencing patient genomes, the researchers found that the axon loss was caused by genetic errors in the gene NMNAT2, whose normal function keeps SARM1 turned off. Due to these genetic errors, SARM1 is constantly activated, which triggers axon destruction. The researchers used the CRISPR gene-editing technique to reproduce these mutations in mice. Like people with the syndrome, these mice survived to adulthood but had worsening motor dysfunction, loss of peripheral axons and, importantly, an infiltration of immune cells called macrophages.

A study suggests that SARM1 not only contributes directly to axon loss but also plays a role in driving neuroinflammation that only serves to compound the problems. The findings also suggest that some neurodegenerative conditions could be treated with immune modulating drugs that block macrophages or other inflammatory immune cells.

New study shows potential to block nerve loss in neurodegenerative diseases

The researchers investigated the possible role of SARM1 in Charcot-Marie-Tooth disease type 2a, a common form of inherited peripheral neuropathy and a good model to study axon loss generally. Patients with this disease have progressive loss of motor and sensory axons and develop difficulty walking, muscle weakness, and tingling or burning sensations in the hands and feet.

The disease is caused by a mutation in an important protein in mitochondria, the energy factories of cells. The mutation, in a protein called mitofusin2, impairs the normal function of mitochondria. Much research has focused on the abnormal mitochondria, assuming they must be the root of the problem in this disease.

Surprisingly, the researchers found that deleting SARM1 in a rodent model of Charcot-Marie-Tooth disease type 2a stopped most of the problems the animals exhibited, independent of the diseased mitochondria. Eliminating SARM1 blocked or slowed axon death, muscle atrophy, mitochondrial abnormalities and problems with neuromuscular junctions, where the neurons interface with muscle. Even with the mutant mitofusin2 protein present, deleting SARM1 protected the mitochondria from further degradation and dysfunction.

This was a complete surprise, but we are hopeful it could be relevant in many neurodegenerative diseases where mitochondrial damage is central, such as Parkinson’s disease, as many neurodegenerative diseases have a component of mitochondrial dysfunction.

SOURCE:

Caitlin B. Dingwall, Amy Strickland, Sabrina W. Yum, Aldrin Kay-Yuen Yim, Jian Zhu, Peter L. Wang, Yurie Yamada, Robert E. Schmidt, Yo Sasaki, A. Joseph Bloom, Aaron DiAntonio, Jeffrey Milbrandt (October 26, 2022). Macrophage depletion blocks congenital SARM1-dependent neuropathy. Journal of Clinical Investigation. Retrieved from : https://www.jci.org/articles/view/159800  

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