GBA1 and Parkinson's Disease
An association between glucocerebrosidase (GBA1) gene mutations and Parkinson's disease (PD) was first observed in 2004. It's the most common of the currently known PD genetic mutations and up to 10 percent of people with PD in the United States carry it. GBA1 mutations increase the risk of Parkinson's, but the chance that they will lead to disease is fairly low. So, the vast majority of people with a mutation will not develop PD. Certain populations, including those of Ashkenazi Jewish descent, are more apt to have GBA1 mutations. And, people with Gaucher disease, a rare condition that causes fatty substances to build up and organs to swell, occurs when two copies of a GBA1 mutation are inherited. (People with PD who carry a GBA1 mutation only have one abnormal copy.)
The GBA1 Gene and the GCase Protein
The GBA1 gene directs the production of the glucocerebrosidase (GCase) protein, which plays a role in the cells' garbage disposals, called lysosomes. GCase breaks down substances called glycolipids. When the GBA1 gene is altered, GCase protein activity decreases, and levels of glycolipids and abnormal proteins, such as misfolded alpha-synuclein protein, rise. Increased alpha-synuclein clumps -- Lewy bodies -- are the hallmark of PD. They are found in the brains of nearly everyone with PD and are thought to cause dopamine cell death. It may be that when not enough GCase is available to clear out abnormal alpha-synuclein, it accumulates and harms cells.
GBA-associated Parkinson's Disease
People with Parkinson's who bear the GBA1 mutation (i.e., "GBA-associated Parkinson's") typically show the classic symptoms of PD -- resting tremor, slowness and stiffness. On the outside, they might be indistinguishable from people with idiopathic Parkinson's, or PD that doesn't have a known genetic or other cause. On postmortem examination, their brains may contain similar amounts of Lewy bodies (alpha-synuclein clumps) as well. GBA-associated Parkinson's often manifests at a younger age, though, and may cause more significant cognitive (memory or thinking) impairment. The motor and non-motor symptoms of GBA-associated Parkinson's are currently treated with the same medications as other forms of Parkinson's. However, the first clinical trial testing a therapy in people with Parkinson's who carry a GBA1 mutation is underway. (Read more about this in the next section.)
MJFF's Role in GBA1 Research
Studying GBA1 mutations is leading to better knowledge of Parkinson's disease mechanisms and ways to potentially slow or stop its progression. The link to alpha-synuclein, one evidenced by pre-clinical and clinical research, is of particular interest because this may have implications for the broad population of people with Parkinson's, regardless of genetic status.
MJFF has supported both pre-clinical and clinical work in GBA1 since 2006. And, the MJFF-led Parkinson's Progression Markers Initiative (PPMI), an observational clinical study to validate biomarkers of PD, is recruiting people with the GBA1 mutation to learn more about how disease unfolds in this population. We've covered a lot of ground, but questions remain and we're working on several fronts to gain clarity. MJFF's strategic roadmap for GBA involves:
- deciphering the biological function and dysfunction of GBA1 as well as its interaction with other PD-relevant genes (e.g., alpha-synuclein and LRRK2),
- increasing understanding of the clinical symptoms of GBA-associated Parkinson's and links to idiopathic (no known cause) PD, and
- promoting development of novel therapeutic approaches targeting the GBA1 pathway, including those that may help the general Parkinson's community (i.e., more than just those who carry a GBA1 mutation).
In 2016, MJFF funded the GBA Meta-Analysis Initiative to: i) gain a deeper understanding of the relationship between GBA1 mutations and the symptoms of GBA-associated Parkinson's and ii) aid researchers in assembling the necessary tools and information for innovative, biomarkers-guided Phase II trials in people with GBA-PD.
While nuances are sorted and general challenges are addressed, great strides are being made. A lipid-lowering drug designed specifically for people with GBA-associated Parkinson's is currently in Phase II clinical testing. If proven, this could be the first personalized medicine for PD. (Watch a webinar to learn more about personalized medicine in Parkinson's.)
GBA research and drug development is forging ahead, and with it so is our understanding of Parkinson's disease and what it takes to achieve success around therapies for GBA1 and other targets in PD.
Play a Part in PPMI
PPMI, MJFF's flagship study, is studying the connection between PD and the GBA gene and needs volunteers.
Find out more about Genetics and PD