Researchers help the brain make GM1 ganglioside, a protective substance that is diminished in the brains of Parkinson’s patients.

Although a number of treatments exist to alleviate the symptoms of Parkinson’s disease, to date, none reliably slow the progression of the disease. In 2013, a molecule called GM1 ganglioside showed promise in patients for not only relieving symptoms but also slowing disease progression. However, GM1 ganglioside has been difficult to make and to deliver to patients for regular use. Now, researchers at Thomas Jefferson University have demonstrated a way to help the brain of mice produce more of its own GM1 ganglioside in a study published December 2nd in the open access journal PLOS ONE.

“GM1 ganglioside has shown great promise in Parkinson’s patients,” says lead author Jay Schneider, Ph.D., Professor in the Department of Pathology, Anatomy and Cell Biology at the Sidney Kimmel Medical College at Thomas Jefferson University. “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 made by nerve cells in the brain, but the substance is made at much lower levels in patients with Parkinson’s and other neurodegenerative diseases. Although earlier work showed that patients who were administered GM1 ganglioside showed improvement in symptoms and progression, the current industry standard for obtaining GM1 ganglioside is to extract the substance from cow brains, which presents a number of manufacturing and potential safety concerns. Also, the substance cannot be readily made synthetically. “We were thinking, ‘there’s got to be a way around this,’” says Dr. Schneider, “instead of putting more GM1 into the brain, why not try to get the brain to make more of it.”

Through a search of existing literature, Dr. Schneider and colleagues found that an enzyme called sialidase was capable of converting other naturally occurring ganglioside molecules in the brain into GM1 ganglioside. They tested their idea in a mouse model of Parkinson’s disease. After the researchers inserted a pump that continually injected the sialidase into the mouse brain, the researchers then simulated the onset of Parkinson’s. In this mouse Parkinson’s model, Dr. Schneider and colleagues saw neuronal protection at similar levels to those seen in mice injected directly with GM1 ganglioside.

Image shows stained slices from the experiment. The caption best describes the image.

“We were very excited to see that this could work in the mouse model,” says Dr. Schneider. “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,” he added.

Creating better ways of enhancing GM1 ganglioside levels in the brain could prove beneficial in a number of diseases in addition to Parkinson’s disease, such as in Huntington’s disease and Alzheimer’s disease. Dr. Schneider is currently investigating novel gene-therapy approaches that could enhance the GM1 ganglioside content of neurons and plans to investigate the neuroprotective potential of these approaches. Provisional patents on these technologies have been filed.

ABOUT THIS PARKINSON’S DISEASE RESEARCH

Funding: This research was supported by the Michael J Fox Foundation. The authors report no conflicts of interest.

Source: Thomas Jefferson University
Image Source: The image is credited to Schneider et al./PLOS ONE
Original Research: Full open access research for “Intraventricular Sialidase Administration Enhances GM1 Ganglioside Expression and is Partially Neuroprotective in a Mouse Model of Parkinson’s Disease” by Jay S. Schneider, Thomas N. Seyfried, Hyo-S. Choi, and Sarah K. Kidd in PLOS ONE. Published online December 2 2015 doi:10.1371/journal.pone.0143351


Abstract

Intraventricular Sialidase Administration Enhances GM1 Ganglioside Expression and is Partially Neuroprotective in a Mouse Model of Parkinson’s Disease

Background

Preclinical and clinical studies have previously shown that systemic administration of GM1 ganglioside has neuroprotective and neurorestorative properties in Parkinson’s disease (PD) models and in PD patients. However, the clinical development of GM1 for PD has been hampered by its animal origin (GM1 used in previous studies was extracted from bovine brains), limited bioavailability, and limited blood brain barrier penetrance following systemic administration.

Objective

To assess an alternative therapeutic approach to systemic administration of brain-derived GM1 to enhance GM1 levels in the brain via enzymatic conversion of polysialogangliosides into GM1 and to assess the neuroprotective potential of this approach.

Methods

We used sialidase from Vibrio cholerae (VCS) to convert GD1a, GD1b and GT1b gangliosides to GM1. VCS was infused by osmotic minipump into the dorsal third ventricle in mice over a 4-week period. After the first week of infusion, animals received MPTP injections (20 mg/kg, s.c., twice daily, 4 hours apart, for 5 consecutive days) and were euthanized 2 weeks after the last injection.

Results

VCS infusion resulted in the expected change in ganglioside expression with a significant increase in GM1 levels. VCS-treated animals showed significant sparing of striatal dopamine (DA) levels and substantia nigra DA neurons following MPTP administration, with the extent of sparing of DA neurons similar to that achieved with systemic GM1 administration.

Conclusion

The results suggest that enzymatic conversion of polysialogangliosides to GM1 may be a viable treatment strategy for increasing GM1 levels in the brain and exerting a neuroprotective effect on the damaged nigrostriatal DA system.

“Intraventricular Sialidase Administration Enhances GM1 Ganglioside Expression and is Partially Neuroprotective in a Mouse Model of Parkinson’s Disease” by Jay S. Schneider, Thomas N. Seyfried, Hyo-S. Choi, and Sarah K. Kidd in PLOS ONE. Published online December 2 2015 doi:10.1371/journal.pone.0143351