Parkinson’s Therapy Aims to Get Brain to Produce Beneficial Molecule

In a recent study in the journal PLOS ONE, researchers from the Thomas Jefferson University demonstrate a way of helping the brain produce more of its own GM1 ganglioside, a molecule that has shown promise in relieving Parkinson’s symptoms and slowing disease progression.

Numerous preclinical studies have shown that the administration of GM1 ganglioside, a major component of plasma membrane lipid raft signaling domains, results in significant biochemical and behavioral recovery following different types of nervous system lesions, including those in animal models of Parkinson’s disease (PD). “GM1 ganglioside has shown great promise in Parkinson’s patients,” lead author Jay Schneider, PhD, a professor in the Department of Pathology, Anatomy and Cell Biology at the Sidney Kimmel Medical College, said in a news release. “However, considering the difficulties with the manufacture of GM1 and its delivery to the brain, we wanted to see if we could coax the brain to make more of its own GM1.”

GM1 ganglioside is normally produced by brain nerve cells. However, in patients with PD and with other neurodegenerative conditions, the substance is made at much lower levels than are seen in healthy people.

Previous studies have shown that patients given the GM1 ganglioside had clear symptom and disease improvements, but for these studies, the molecule was extracted from cow brains — an approach with both manufacturing challenges and safety concerns. GM1 ganglioside cannot be readily made synthetically. “We were thinking, ‘There’s got to be a way around this,'” said Dr. Schneider. “Instead of putting more GM1 into the brain, why not try to get the brain to make more of it?”

In the study, titled “Intraventricular Sialidase Administration Enhances GM1 Ganglioside Expression and Is Partially Neuroprotective in a Mouse Model of Parkinson’s Disease,” Dr. Schneider and colleagues conducted a search of existing literature and found that an enzyme known as sialidase was able to convert natural ganglioside molecules in the brain into GM1 ganglioside. Investigators then looked at an alternative therapeutic approach for systemic administration of brain-derived GM1, with the intent of increasing GM1 levels in a mouse model while assessing the substance’s neuroprotective potential. The team inserted a pump that constantly injected sialidase into the animals’ brains. They then initiated the onset of PD in the mice, and observed a neuronal protection at levels identical to those displayed in mice injected directly with GM1 ganglioside.

“We were very excited to see that this could work in the mouse model,” said Dr. Schneider, adding that further efforts are underway. “As long-term delivery of sialidase enzymes to the brain would require implantation of a pump system, which might not be optimal, we are currently working on alternative gene therapy approaches to enhance GM1 levels in the brain.”

A clinical way of increasing GM1 ganglioside levels in the brain could potentially benefit patients with other diseases, including Huntington’s and Alzheimer’s. Dr. Schneider is currently studying gene-therapy methods that could enhance the GM1 ganglioside content of neurons and their neuroprotective potential. For now, provisional patents on the  technologies have been filed.