Researchers at the University of Alberta have identified a new, critical function for a unique class of brain molecules that are part lipid and part sugar, opening a new avenue for understanding and potentially treating neurodegenerative diseases. The study, published in Science Advances, clarifies how these molecules, known as gangliosides, facilitate essential communication between neurons and help clear cellular waste, processes that are impaired in conditions such as Huntington’s disease and Parkinson’s disease.

The findings pinpoint the role of gangliosides in the formation and release of extracellular vesicles, which are tiny particles that act as the brain’s messengers and sanitation workers. By demonstrating that low levels of these lipids disrupt this vital system and lead to the accumulation of toxic proteins, the research provides a new framework for developing therapies aimed at restoring normal brain function. Earlier work by the same lab had already shown that replenishing a specific ganglioside, GM1, could reverse symptoms of Huntington’s in mouse models, and this new discovery explains the mechanism behind that success.

A Dual-Function Molecule

For decades, scientists have worked to understand the complex environment of the brain, where lipids make up about half of the brain’s dry weight. Among these are gangliosides, complex molecules that are a hybrid of fats and sugars. The new research has uncovered an unexpected and fundamental role for these molecules. “Our recent study has uncovered a quite unexpected role for these fascinating molecules that are half fat and half sugar,” stated principal investigator Simonetta Sipione, a professor of pharmacology at the University of Alberta.

These molecules are essential components of the neuronal cell membrane, contributing to the structural integrity and fluidity necessary for proper electrical signaling. The lipid portion helps form the cell’s outer boundary, while the sugar chains extend outward, participating in cell-to-cell recognition and communication. The study reveals that their function goes beyond structural support, directly enabling the machinery that neurons use to communicate with each other and maintain a healthy internal environment. This discovery positions gangliosides as a key player in the intricate processes that support neuronal health.

The Role of Extracellular Vesicles

The core of the discovery lies in the relationship between gangliosides and extracellular vesicles. These small, membrane-bound particles are released by cells to transport proteins, lipids, and nucleic acids to neighboring cells, serving as a critical form of intercellular communication. Additionally, they are used by cells to package and eject unwanted material, acting as a microscopic waste disposal system.

The University of Alberta team demonstrated that the production and release of these vesicles are dependent on adequate levels of gangliosides. When ganglioside levels are low, this entire system falters. Without efficient vesicle formation, neurons struggle to both send signals and clear out aggregated, misfolded proteins. This breakdown is a hallmark of many neurodegenerative disorders, where the buildup of toxic proteins leads to cell dysfunction and, eventually, cell death.

Implications for Neurodegenerative Disease

The research has significant implications for several devastating neurological conditions. Huntington’s disease, an inherited disorder that causes the progressive breakdown of nerve cells in the brain, is a primary example. One in every 7,000 Canadians is affected by the disease, which is caused by a mutant huntingtin protein that misfolds and clumps inside neurons.

The study provides a direct link between low ganglioside levels and the pathology of the disease. “Now we know that when gangliosides are low—not just in Huntington’s disease but also in Parkinson’s and in other hereditary neurodegenerative diseases—the vesicle-mediated cell communication and clearance system doesn’t work properly,” Sipione explained. “This allows harmful proteins such as mutant huntingtin to accumulate and thus contributes to the processes that drive neurodegeneration.” This insight helps explain why the accumulation of toxic proteins is so damaging and offers a new target for intervention: restoring the vesicle system by addressing the ganglioside deficiency.

From Animal Models to Human Therapy

The therapeutic potential of this discovery is supported by the team’s previous research. In earlier studies, the scientists found that restoring levels of the ganglioside GM1 in mice bred to model Huntington’s disease led to a reversal of their symptoms. While the initial results were promising, the underlying reason for the improvement was not fully understood. The new findings provide the missing piece of the puzzle, showing that GM1 restoration likely works by fixing the faulty extracellular vesicle system.

This mechanistic understanding is a crucial step in translating the findings from laboratory animals to human patients. By knowing how the treatment works, researchers can better design drugs and monitor their effectiveness in clinical trials. Sipione is collaborating with a biotech company to explore this possibility, with the ultimate goal of developing a ganglioside-based therapy that can slow or halt the progression of neurodegenerative diseases.

Overcoming the Blood-Brain Barrier

A Major Hurdle in Treatment

Despite the promise of ganglioside therapies, a significant challenge remains: the blood-brain barrier. This protective layer of cells tightly controls which substances can pass from the bloodstream into the brain, and it effectively blocks most of the gangliosides administered through conventional injections. This means that delivering a therapeutically effective dose to the brain is difficult.

Potential Delivery Solutions

Researchers are actively investigating alternative methods to bypass this barrier. Several innovative approaches are being considered to ensure that a sufficient concentration of the therapeutic molecules reaches the intended target within the brain. These potential solutions include:

• Nanoparticles: Encasing the gangliosides in tiny engineered particles could allow them to be ferried across the blood-brain barrier.
• Intranasal Sprays: Administering the therapy through the nasal passages may provide a more direct route to the brain, circumventing the barrier.
• Spinal Injections: Delivering the treatment directly into the cerebrospinal fluid that surrounds the brain and spinal cord would also bypass the bloodstream barrier entirely.

Sipione and her team will continue to investigate these delivery methods while working to fully understand the complete picture of how gangliosides protect the brain. Determining the most effective and safest way to administer the therapy will be critical for its potential future use in patients.