Some of the most debilitating human diseases – like Huntington’s disease – are caused by a mutation in just one of your roughly twenty thousand genes. Huntington’s is a fatal progressive neurodegenerative disorder, but despite knowing the gene that causes the disease, scientists have yet to find a cure or even an effective treatment.
A group of scientists from the University of Alberta are making progress, however. They’ve discovered a molecule that acts as a modifier for Huntington’s disease, slowing disease progression.
Huntington’s disease is caused by a repetitive expansion of a gene that produces a protein called huntington. The defectively elongated gene produces a similarly elongated and defective protein, which aggregates in the brain. These clumps of huntington protein eventually lead to the uncontrolled jerking body movements that characterize the disease as well as a variety of cognitive and psychiatric symptoms.
The University of Alberta scientists, led by Dr. Simonetta Sipione, identified a type of lipid called a ganglioside, specifically the ganglioside GM1, that slowed the progression of neurodegeneration and improved the disease symptoms in mouse models of Huntington’s disease.
This new research builds off previous work the group published in 2010, where they found that cells from human Huntington’s patients had deficits in GM1 production. The scientists noticed that the reduced GM1 levels were making these cells particularly vulnerable to a process called apoptosis, or programmed cell death.
Furthermore, when they artificially reduced levels of GM1 in healthy cells, the cells quickly started to resemble the cells from Huntington’s disease patients. This led Sipione and her colleagues to speculate that defective GM1 synthesis might be a causative factor in the pathogenesis of Huntington’s disease.
In their latest article, published in EMBO Molecular Medicine, Sipione builds upon this theory, asking “can the symptoms of Huntington’s disease be improved by restoring GM1 to a healthy level?”
To answer this question, the scientists treated three different mouse models that together capture the whole spectrum of Huntington’s disease symptoms with GM1. The results were striking: all the symptoms that make Huntington’s disease a devastating illness – the debilitating movement deficits, the cognitive impairments, the psychiatric problems – were significantly improved with sustained GM1 administration. Increasing GM1 had a direct impact on the mutant huntington protein as well, markedly reducing its presence in the treated brains.
Sipione and her team recognize that while treatment with GM1 is not a cure for Huntington’s disease, it has the potential to be a powerful disease-modifying therapy. GM1 could alleviate the core symptoms of Huntington’s while simultaneously slowing the progression of the disease – something the University of Alberta scientists stress is urgently needed given the current lack of viable treatments.
This isn’t the first time GM1 has been explored therapeutically. In fact, several clinical trials have been completed testing GM1 as a treatment for Parkinson’s disease. In these trials, GM1 was able to significantly slow the progression of Parkinson’s symptoms. Critically, these trials show not only that GM1 can be effective therapeutically, but that it is safe for use in patients.
This may expedite the ultimate goal of the University of Alberta researchers – the translation of these new results into a clinical trial for Huntington’s disease.
