Home » Exploring new therapy options for ALS: Gasdermine and the Sigma-1 receptor investigations

Exploring new therapy options for ALS: Gasdermine and the Sigma-1 receptor investigations

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While there are drugs on the market to slow the progression of neurodegenerative diseases, there is no cure yet. But researchers at Boston Children’s Hospital and Harvard Medical School are looking for new ways to slow neuronal dysfunction and treat amyotrophic lateral sclerosis (ALS). The team found that proteins involved in the innate immune system could be at the root of the disease; and that inactivation of a protein in the brain, called gasdermin E, linked to inflammation prevents cell damage in human neurons and delays the progression of ALS in mice. When cells recognize danger, such as an infection, immune molecules recruit immune cells to the site of damage to try to eliminate it and repair tissue. Sometimes, the immune response involves a family of proteins called gasdermines, which cause cells to die through a highly inflammatory process called pyroptosis.

One type of gasdermine, gasdermine E, is expressed most highly in nerve cells in the brain. But no one knew what he was doing. The research team first looked at how gasdermine E affects neurons. The team developed models of neurons from mouse and human samples and examined the effects of gasdermine E on axons, or the parts of neurons that send electrical signals. The researchers found that when neurons sense danger, gasdermin E causes damage to cell mitochondria and axons. Axons degenerate, but cells do not die. This retraction occurs in the nerves of the muscles of ALS patients, which begins with muscle twitching and weakness, but eventually progresses to muscle atrophy and paralysis. To better understand the relationship between neurodegeneration and gasdermin E, the team created models of ALS motor neurons by transforming stem cell samples from ALS patients into neurons.

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The researchers found that gasdermin E is present at high levels in these neurons. And it could protect axons and mitochondria from damage by genetically silencing gasdermin E in a mouse model of ALS. The team therefore wanted to see if the effects observed in the cells could translate into improvements in symptoms related to neurodegeneration. They found that the protein delayed the progression of symptoms and led to protected motor neurons, longer axons and lower overall inflammation. These results suggest that gasdermine E causes changes in neurons that may contribute to disease progression. Although some drugs can block the effects of other gasdermines, it is still unclear whether gasdermine E can be targeted with drugs. This work could be an important first step towards developing new approaches for the treatment of ALS. But there is the possibility of conditioning the mitochondria with other proteins that have drugs.

One of these is the sigma-1 receptor, a membrane protein that localizes to cell organelle membranes and regulates fat metabolism, protein transport, and more. Some data would indicate that some of its mutations could be responsible for juvenile-onset forms of ALS. Organelle contact sites are multifunctional platforms for maintaining cellular homeostasis. Mitochondria-associated membrane (MAM) alternations, one of the contact sites of the organelles where the endoplasmic reticulum is bound to the mitochondria, have been implicated in the pathogenesis of some neurodegenerative diseases, including ALS. The ATPase protein ATAD3A is a basic protein in MAMs. Sigma-1 receptor also localizes in the MAM; new data would indicate that the sigma-1 receptor requires ATAD3A to keep these membranes intact and maintain ATAD3A as a monomer and not a polymer,

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This is associated with an inhibition of mitochondrial fragmentation. ATAD3A dimerization and mitochondrial fragmentation were significantly observed in ALS mouse spinal cords deficient in sigma-1 receptor or linked to SOD1 mutations. Thus targeting the Sigma1-ATAD3 protein axis could be an additional modality to treat ALS in the future. The sigma receptor, in fact, enjoys the advantage of binding dozens of molecules and drugs developed since the 1980s to study its biological functions. These include opioid molecules such as pentazocine, neurosteroids such as allopregnenolone, hallucinogenic molecules such as PCP and dimethyltryptamine, the antipsychotic haloperidol, and even anti-vomiting and antihistamine agents such as chlorpheniramine and dimenhydrinate. Finding the right agent among these could greatly facilitate the expansion of the therapeutic arsenal of this deadly disease.

  • By Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific publications

Neel DV, Basu H, Gunner G et al. Neuron. 2023 Mar 3.

Watanabe S et al. Neurobiol Dis 2023 Apr; 179:106031.

Wei Y, Lan B et al. Nat Commun. 2023 Feb; 14(1):9

Herring GM et al. Brit J Pharmacol. 2021;178(6):1336.

Parakh S, Atkin JD. Semin Cell Dev Biol. 2021; 112:105.

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