Researchers from Boston Children’s Hospital and Harvard Medical School are investigating novel approaches to slow the progression of neurodegenerative diseases and treat amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease.

Despite drugs being available to slow disease progression, no cures have been discovered. The researchers have uncovered a possible link between proteins associated with the innate immune system and neuronal dysfunction, offering new pathways for treatment.

“The unmet need for therapies for neurodegenerative diseases is huge,” remarks co-author Judy Lieberman, “and our work opens up a whole new pathology that we could address.”

Co-principal investigator Isaac Chiu says that they have found “an innate immune molecule playing a role in neurodegeneration,” which could “opens up a new avenue for thinking about neuronal health.”

In a significant breakthrough, researchers have discovered that deactivating a molecule in the brain, which is associated with inflammation, can delay the progression of ALS in mice and prevent cellular damage in human neurons.

These findings were just published in Neuron.

Inflammatory proteins’ function in the brain

When cells sense a threat such as an infection, the immune system springs into action by activating immune molecules. This process recruits and stimulates immune cells to the affected area, attempting to eliminate the danger and coordinate tissue repair. Gasdermins, a family of proteins, can sometimes be involved in this immune response, causing cells to die through a highly inflammatory process known as pyroptosis. Gasdermin E, a specific type of gasdermin, is most highly expressed in nerve cells within the brain. However, until now, researchers were unsure about its function.

To investigate the impact of gasdermin E on neurons, the team, led by Dr. Lieberman and Chiu, created models of neurons using both mice and human samples and examined how gasdermin E affected the axons, which are responsible for transmitting electrical signals in neurons. Their findings revealed that when neurons sense a threat, gasdermin E triggers damage to the mitochondria, the powerhouse of the cell, and the axons. As a result, the axons start to break down, but the cells themselves do not perish.

“If you look at a plate of neurons,” explains lead author Himanish Basu, “you see a jungle of axons. But if you look at a plate where gasdermin E is activated, you see retractions of these cellular processes.”

Patients with ALS, a degenerative condition marked by muscular twitching and weakening but ultimately advancing to muscle atrophy and paralysis, experience this retraction in the nerves in their muscles.

This “study is an example of how immunology can help explain neurodegeneration on a mechanistic level, and what drives axon loss and neuronal injury,” remarks co-author Dylan Neel.

ALS and Gasdermin E

In an effort to further explore the link between gasdermin E and neurodegeneration, the research team developed models of ALS motor neurons using stem cell samples from ALS patients. Through this research, they discovered that gasdermin E is present at high levels in these neurons, and by silencing gasdermin E, they were able to protect axons and mitochondria from damage.

In order to test whether these cellular effects could translate to improvements in symptoms related to neurodegeneration, the researchers silenced gasdermin E in a mouse model of ALS. They observed that this delay in the progression of symptoms led to protected motor neurons, longer axons, and less overall inflammation. The team’s findings suggest that gasdermin E could play a critical role in driving changes to neurons that contribute to disease progression, and may hold promise as a target for future therapies.

“Inflammation is a double-edged sword, and could be very destructive based on context,” remarks Chiu.

The effectiveness of targeting gasdermin E with drugs to treat ALS remains unclear, despite drugs being available that can block other gasdermins’ effects. However, the findings represent a crucial initial stride towards developing novel treatment methods for ALS.

“We describe a pathway and molecules that you can target for treating many neurodegenerative diseases,” adds Dr. Lieberman.

Source: 10.1016/j.neuron.2023.02.019

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