New immune pathway sheds light on ALS

Summary: A recent study reveals that certain proteins, commonly associated with inflammation and immunity, can damage our neurons, contributing to ALS.

Source: Boston Children’s Hospital

While drugs are on the market to slow the progression of neurodegenerative diseases, there are still no cures. 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), a deadly motor neuron disease.

The team discovered that proteins involved in the innate immune system could be the cause of the disease.

“The unmet need for therapies for neurodegenerative diseases is enormous, and our work opens up a whole new pathology that we could address,” says Judy Lieberman, MD, PhD, researcher in Boston Children’s Cellular and Molecular Medicine Program and a co-principal investigator of the project.

“We revealed an innate immune molecule with a role in neurodegeneration, opening a new avenue of thinking about neuronal health,” says Isaac Chiu, PhD, associate professor of immunology at Harvard Medical School and co-principal investigator. of the project.

Researchers have found that inactivating a molecule in the brain linked to inflammation prevents cell damage in human neurons and delays the progression of ALS in mice.

The findings will be published in Neuron.

The role of inflammatory proteins in the brain

When cells recognize danger, such as an infection, immune molecules are activated to trigger an alarm that recruits and activates immune cells at the site of damage in an attempt to eliminate them and orchestrate tissue repair.

Sometimes the immune response involves a family of proteins called gasdermins, which trigger cell death through a highly inflammatory process called pyroptosis. One type of gasdermin, gasdermin E, is expressed in the brain most strongly in nerve cells. But no one knew what he was doing.

The research team, led by Dr. Lieberman and Chiu, first looked at how gasdermin E affects neurons. The team developed models of neurons from mice and human samples and examined the effects of gasdermin E on axons, or the parts of neurons that send electrical signals.

The researchers found that when neurons sense danger, gasdermin E damages the cell’s powerhouse, called the mitochondria, and the axons. The axons degenerate, but the cells do not die.

“If you look at a plate of neurons, you see a jungle of axons. But if you look at a plaque where gasdermin E is activated, you see retractions of these cellular processes,” says Himanish Basu, a postdoctoral researcher in Chiu’s lab at Harvard University who led the study.

This retraction occurs in the nerves of muscles in patients with ALS, a progressive disease characterized by muscle twitching and weakness, but eventually progressing to muscle atrophy and paralysis.

This shows a brain in the style of Van Gogh
Researchers have found that inactivating a molecule in the brain linked to inflammation prevents cell damage in human neurons and delays the progression of ALS in mice. Credit: Neuroscience News via DALE-E 2

“Our study is an example of how immunology can help explain neurodegeneration at the mechanistic level, and what leads to axon loss and neuronal damage,” says Dylan Neel, MD/PhD student in the lab of Chiu who co-directed this study.

Gasdermin E in ALS

To better understand the relationship between gasdermin E and neurodegeneration, the team created models of ALS motor neurons by transforming stem cell samples from ALS patients into neurons. The researchers found that gasdermin E is present at high levels in these neurons. And they could protect axons and mitochondria from damage by silencing gasdermin E.

The team then wanted to test whether the effects observed in the cells could translate into an improvement in symptoms linked to neurodegeneration. Researchers silenced gasdermin E in a mouse model of ALS. They found that it delayed the progression of symptoms and resulted in protected motor neurons, longer axons and less overall inflammation.

These results suggest that gasdermin E causes changes in neurons that may contribute to disease progression. “Inflammation is a double-edged sword and could be very destructive depending on the context,” says Chiu.

Although some drugs can block the effects of other gasdermins, it is still unknown whether gasdermin E can be targeted by drugs. But this work is an important first step toward developing new approaches to treating ALS. “We describe a pathway and molecules that you can target to treat many neurodegenerative diseases,” says Dr. Lieberman.

About this ALS research news

Author: Gina Mantic
Source: Boston Children’s Hospital
Contact: Gina Mantica – Boston Children’s Hospital
Picture: Image is credited to Neuroscience News and created with DALL-E 2 AI technology

Original research: The findings will appear in Neuron

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