Researchers have discovered a mechanism through which toxic protein clusters develop in the brain in Parkinson's disease. It may be treatable with drugs approved for another disease.

In a paper published in the journal Neuron, the scientists describe how they discovered that increasing a fatty substance, or lipid, called glucosylceramide causes a buildup of toxic clusters of alpha-synuclein protein inside dopamine-producing brain cells.

The team also revealed that treatment with an already approved glucosylceramide synthase inhibitor—a drug that reduces production of the lipid—reduced the toxic protein clusters, which are a hallmark of Parkinson's disease.

"Some companies," says senior study author Joseph Mazzulli, an assistant professor of neurology at Northwestern University Feinberg School of Medicine in Chicago, IL, "have been using synthase inhibitors to reduce the synthesis of the lipid, and we used a similar compound on patient-derived neurons in our study."

"We were able to show it reduced toxic alpha-synuclein aggregation directly within neurons derived from Parkinson's patients," he adds.

Parkinson's arises from dopamine cell death

Parkinson's disease is a progressive condition that arises from the death of cells in a brain region known as the substantia nigra. The cells produce a chemical messenger called dopamine that is important for regulating movement.

The main symptoms of Parkinson's disease are tremors, slowness of movement, and stiffness, as well as reduced balance and coordination. Other symptoms include emotional changes, sleep disruption, depression, difficulty speaking, problems with swallowing and chewing, and constipation.

Parkinson's mostly strikes after the age of 60, although a small number of cases are diagnosed in those under the age of 50. As the symptoms worsen, it gets harder to cope with everyday tasks and lead an independent life.

There are more than 10 million people living with Parkinson's worldwide, including around 1 million in the United States—where approximately 60,000 cases are diagnosed every year—alone.

While there is, as yet, no cure for Parkinson's disease, there are drugs and other treatments that offer symptom relief for many patients.

GBA1 mutations and Parkinson's disease

In the study paper, Professor Mazzulli and team explain that a strong risk factor for the development of toxic alpha-synuclein clusters in Parkinson's is mutations in the glucocerebrosidase (GBA1) gene.

The gene produces a protein that is important for the correct functioning of lysosomes, which are compartments inside cells that break down and clear away glucosylceramide and other lipids.

Those with one mutated copy of GBA1 have higher-than-normal levels of the glucosylceramide and have a greater risk of developing Parkinson's disease.

Having two mutated copies of the gene—one from each parent—can lead to Gaucher's disease, which is a rare disorder wherein lysosomes fail and fatty compounds build up in the body.

However, although it is known that GBA1 mutations are linked—perhaps through the disruption of glucosylceramide clearance—to the development of toxic alpha-synuclein clusters, what has not been clear, until the new study, is the mechanism behind it.

Mutated GBA1 may not be necessary

To investigate, the scientists tested the effects of a drug that raises levels of glucosylceramide in dopamine-producing neurons grown from patient-derived stem cells. The cells did not have mutated forms of the GBA1 gene.

They discovered that even without the mutated gene, there was a significant buildup of toxic alpha-synuclein clusters in the neurons.

Professor Mazzulli suggests that this indicates that the conversion of normal alpha-synuclein into its toxic form did not necessarily depend on "the presence of the mutated GBA1 protein, but more importantly the decreased activity and accumulation of glucosylceramide."

Complex alpha-synuclein and toxic clusters

On closer investigation of the conversion of alpha-synuclein from its normal to toxic form, the team discovered that it was not just the simple form of alpha-synuclein—as previously thought—that converted into a toxic cluster.

Instead, glucosylceramide was directly converting the complex form of alpha-synuclein into toxic clusters. "We were surprised to find that toxic aggregation occurred by direct conversion of the large alpha-synuclein complex," Mazzulli explains.

"We thought," he continues, "[that] the complex would have to first disassemble before forming toxic aggregates, but that's not what our data indicated."

He says that drugs devised for the treatment of Gaucher's disease might be one way to target this mechanism.

These findings also offer a way to measure how well drugs might perform in trials. While the goal of Parkinson's treatment is to reduce alpha-synuclein clusters, measuring levels of the toxic protein in living patients is not straightforward.

"It's far easier to measure the effects of therapeutics that alter glucosylceramide in patients, since the lipid can be directly measured from easily accessible fluids, such as blood or cerebral spinal fluid."

Professor Joseph Mazzulli