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News in Brief

Genetic Risk Factor for Parkinson’s Linked to Increased Alpha-Synuclein

Researchers at the Harvard Medical School in Boston, MA, and the University of Ottawa in Canada, have shed light on a mystery about the relationship between a gene called GBA and Parkinson’s disease (PD).

It was recently discovered that carriers of mutations in this gene are at a higher risk for Parkinson’s, but no one has known why this is so. The new study suggests that the answer may lie in the accumulation in brain cells of alpha-synuclein protein, the hallmark of the disease. The research was published in the April 6 online edition of Annals of Neurology.

Mutations in GBA (the full name is glucocerebrosidase) are the most common genetic risk factor for Parkinson’s.  People who carry mutations in one copy may have up to five times the normal risk of developing PD. In addition, mutations in GBA increase the risk of another neurodegenerative disease, dementia with Lewy bodies (DLB).  When the mutations occur in both copies of a person’s GBA gene, the result is a rare disorder known as Gaucher’s disease. But the role of this gene in the development of PD remained unknown.

In the new study, Valerie Cullen, Ph.D., of Harvard, and Michael G. Schlossmacher, M.D., of the University of Ottawa, and their colleagues set out to understand the molecular pathways that connect GBA mutations with the accumulation of alpha-synuclein. They used a range of laboratory methods to study nerve cells that had GBA mutations, in cell culture as well as mice carrying these mutations.


  • The researchers established, in experiments with nerve cells grown in the laboratory, that alpha-synuclein accumulated in cells with GBA mutations.
  • In separate biochemical studies, they also showed that GBA mutations prevented cells from efficiently breaking down and removing alpha-synuclein.
  • They found, in mice with GBA mutations, that alpha-synuclein levels increased in brain cells as the mice got older. 

What Does it Mean?

While most carriers of GBA mutations do not develop Parkinson’s disease, carrying a mutation does increase the risk for developing Parkinson’s. This new research shows that the mechanism of this increased PD risk is mediated by alpha-synuclein protein build-up in nerve cells, including those that help control the body’s movements. Clusters of alpha-synuclein in these cells are linked to the cell death responsible for PD.

Better understanding of the biology of Parkinson’s may help scientists develop drugs that will modify PD progression. Drugs targeting GBA for the purpose of developing treatments for Gaucher’s disease are already under development. Understanding the link between GBA and PD may prove useful in designing drugs against both Parkinson’s and Lewy body dementia.

Gene Therapy for Advanced Parkinson’s Shows Promise

An experimental surgical treatment for Parkinson’s disease (PD) — which involves inserting the human gene known as GAD deep into a brain structure — improved motor symptoms in people with a moderately advanced stage of Parkinson’s. The results were reported in the March 17 online issue of The Lancet Neurology.

Gene therapy is a method which delivers a therapeutic substance, made by a gene, directly to a specific area of the body. In the new study, scientists used an inactivated virus to deliver the gene called glutamic acid decarboxylase (GAD) into brain cells. GAD makes a neurotransmitter called GABA which can suppress over-activity in an area of the brain called the subthalamic nucleus. (It is this kind of over-activity that contributes to the movement symptoms and complications of Parkinson’s, such as dyskinesia.) An earlier study showed that the use of this virus to deliver the GAD gene into the brain was a safe approach in people with PD.

Investigators at seven US research centers led by Andrew Feigin, M.D., of the Feinstein Institute for Medical Research, North Shore University Hospital, Manhasset, NY, surgically inserted catheters into the brains of 16 study participants to carry the GAD gene to both sides of an area of the midbrain known as the subthalamic nucleus. An additional 21 participants underwent sham surgery, a simulated injection procedure in which the skull is not opened and participants do not receive the GAD gene. Sham surgery is important for research design and helps to maintain “blinding” of the study, meaning neither the participants nor medical personnel know which participants had the “real thing,” and which had the fake procedure.


Six months after the surgery, the motor symptoms in participants who received gene therapy improved by an average of 23 percent, as measured by a standard rating scale, the Unified Parkinson’s Disease Rating Scale (UPDRS). Symptoms in participants who had sham surgery improved by an average of 13 percent. Participants experienced mild to moderate side effects, mainly headache and nausea, but no other adverse consequences.

What Does it Mean?

The idea of injecting a gene into the brain to make a protein to treat PD has long been discussed in the scientific community. This study is the first rigorously designed clinical trial to test that hypothesis, and it is the first double-blinded study to show a positive — albeit very modest — benefit. By comparison, the benefits of the surgical technique known as deep brain stimulation — for a comparable population — are significantly better. It should also be noted that GAD is not a therapy that slows down the progression of PD, an important goal for future gene therapies.

That said, the primary aims of this phase two clinical study were to test the safety, dosage and feasibility of the gene therapy approach. In these aims, the study demonstrated positive results. Thus, this study also offers some encouragement to researchers and people with Parkinson’s, while confirming the need for additional study.