Two new studies from Washington University School of Medicine in St. Louis support development of a broadly applicable treatment for neurodegenerative diseases that targets a molecule that serves as the central executioner in the death of axons, the wiring of the nervous system. Blocking this molecular executioner prevents axon loss, which has been implicated in many neurodegenerative diseases, from peripheral neuropathies to Parkinson’s disease, and glaucoma to amyotrophic lateral sclerosis (ALS). The new studies, both published in the Journal of Clinical Investigation and led by Jeffrey Milbrandt, MD, PhD and professor of genetics, reveal surprising details about how the cellular protein called SARM1 triggers axon death. The research underlies the development of neurodegenerative and points to new therapeutic approaches for diseases defined by axon loss.
In 2017, Milbrandt and co-senior author Aaron DiAntonio, MD, PhD, discovered that SARM1 is an enzyme that can promote neurodegeneration. Soon after, they co-founded a startup company called Disarm Therapeutics to boost the development of drug compounds that inhibit SARM1 for the treatment of diseases characterized by axon degeneration. In 2020, Disarm Therapeutics was acquired by Eli-Lilly Company to further the development of SARM1-targeted therapies for neurodegenerative diseases. In healthy neurons, SARM1 is always switched off. In a healthy axon, SARM1 activity is restrained by the NAD+ biosynthetic enzyme NMNAT2, which converts NMN and ATP into NAD+. NMNAT2 is a highly labile protein produced trafficked into the axons. Nerve injury blocks axonal transport and leads to rapid depletion of axonal NMNAT2, causing NMN buildup and NAD+ cofactor loss.
Recent breakthroughs led to the discovery that SARM1 is activated by an increase in the NMN to NAD+ ratio. NMN and NAD+ can both bind at an allosteric site in the enzyme’s N-terminus to differentially regulate its conformation, and hence, the activation state of SARM1. 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. Certain neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss. One of these toxin is 3-acetyl-pyridine, another is 2-aminopyridine and other aromatic endogenous neurotoxins like quinolinic acid and kynurenine might have the same effects. To understand more the role of SARM1 in axon destruction, the researchers studied a mysterious and extremely rare progressive neuropathy syndromek so rare it still 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 reached the adulthood but had worsening motor dysfunction, loss of peripheral axons and, importantly, an infiltration of macrophages. The researchers were surprised to find that reducing the number of macrophages reversed the axon loss and disease symptoms in the mice.
The study suggests that SARM1 not only contributes directly to axon loss but also plays a role in driving neuroinflammation. The findings also suggest that some neurodegenerative conditions could be treated with immune modulating 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, (CMT2a) 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 called mitofusin-2. The mutation 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 CMT2a stopped most of the problems the animals exhibited, independently of the diseased mitochondria. Eliminating SARM1 blocked or slowed axon death, muscle atrophy, mitochondrial abnormalities and problems with neuromuscular junctions. Even with the mutant mitofusin-2 protein present, deleting SARM1 protected the mitochondria from further degradation and dysfunction. Simple mononucleotides like nicotinic acid monophosphate (NMP) are inhibitors of SARM1. A very similar analogue is orotic acid mononucleotide (OMP), which is produced stoppig pyrimidine sythesis with DHODH inhibitors, drugs used as immune suppressors. Scientists also deem SARM1 as a candidate mediator of environmental neurotoxicity and suggest that SARM1 agonists could be useful as selective agents for neurolytic therapy.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Dingwall CB et al. J Clin Invest. 2022 Oct 26; e159800.
Yamada Y et al. J Clin Invest. 2022 Oct 26; e161566.
Wu T, Zhu J et al. Cell Rep 2021 Oct 19; 37(3):109872.
Figley MD, Gu W et al. Neuron. 2021; 109(7):1118-36.
Figley MD, DiAntonio A. Curr Opin Neurobiol. 2020; 63:59.
Dott. Gianfrancesco Cormaci
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