Gaucher disease is an inheritable metabolic disorder caused by a malfunctioning enzyme, called glucocerebrosidase, that’s needed to break down, or metabolize, a specific fatty material. Over time, harmful amounts of this substance can accumulate in various cells and tissues in the body. This can damage a person’s bones, liver, and spleen. Children with type 2 Gaucher disease can also have extensive damage to the brain, whereas those with type 1 do not.
Gaucher disease occurs when a person inherits 2 defective copies of the GBA gene, which codes for glucocerebrosidase. People with even one mutation in GBA also have a higher risk of developing Parkinson’s disease—a disorder characterized by tremors, muscular rigidity, and slowed movements. People with Parkinson’s disease lose the cells involved in movement (dopamine neurons) and accumulate a protein called alpha-synuclein in their brains.
To better understand the dysfunctional enzyme’s role in Parkinson’s disease, a team led by Dr. Ellen Sidransky at NIH’s National Human Genome Research Institute (NHGRI) compared cells from patients who have Gaucher disease, with and without Parkinson’s disease, and healthy adults. The researchers converted skin cells into dopamine neurons. They then evaluated the enzyme’s activity and the levels of the fatty material and alpha-synuclein. Results were published on July 13, 2016, in the Journal of Neuroscience.
Neurons from patients with type 1 Gaucher disease who also have Parkinson’s disease and those with type 2 Gaucher disease showed reduced enzyme activity and increased levels of alpha-synuclein and the fatty material compared with healthy adult cells. Neurons from patients with type 1 Gaucher disease without Parkinson’s disease showed similar results, but lacked alpha-synuclein accumulation.
The team next tested a small “chaperone” molecule called NCGC607 on the neurons. The molecule, which they had identified in previous work, improves the activity of glucocerebrosidase. The chaperone restored the enzyme’s ability to gain entry into lysosomes—the cell compartment where fatty materials are broken down—and increased enzyme activity. After treatment, dopamine neurons from patients with type 2 and type 1 Gaucher disease with Parkinson’s disease also showed less buildup of the fatty material and alpha-synuclein. These findings suggest that using a molecular chaperone to aid the dysfunctional enzyme may be a useful strategy for treating both diseases.
“This research demonstrates how insights from a rare disorder such as Gaucher disease can have direct relevance to the treatment of common disorders like Parkinson’s disease,” says NHGRI scientific director Dr. Daniel Kastner. More research is needed to determine whether using such a small molecule could be useful for treating either disease.