Last week, The Michael J. Fox Foundation (MJFF) hosted a workshop to delve deeper into understanding how specific mutations in a gene called glucocerebrosidase (GBA) might cause Parkinsonís disease (PD).† The group met in New York to make recommendations as to what the research field can do to continue to drive forward drug compounds targeting GBA.
Since first being tied to Parkinsonís in 2008, research has pointed to GBA as the most common genetic risk factor linked to the clumping of the protein alpha-synuclein that takes place in all people with the disease.† But itís hard to tell exactly what this means; researchers still donít recognize why, or how, mutations in GBA might lead to this alpha-synuclein aggregation.
Hereís what scientists do know:
GBA is an enzyme found in cellular subunits called lysosomes, which are basically garbage disposals designed to break down and dispel certain unwanted fats called from within our cells.† Mutations in GBA seem to cause these lysosomes to lose their ability to get rid of these fats, and this can cause complications.†
And hereís what scientists have hypothesized:
In Gaucherís disease, which is caused by mutations in the GBA gene, too many of these fats cause the liver and spleen to become enlarged.† In PD, itís believed that their presence might lead to alpha-synuclein build-up, and also, to the progressive cell death in the brain that is common to Parkinsonís.
Still, scientists wonder, is this alpha-synuclein aggregation tied to mutations in GBA due to the mutation in the gene itself, or, as noted above, could it be a response to the extraneous build-up of these fats?†
Researchers have more to do to nail down the true nature of the culprit.† Better understanding whatís at work is crucial to developing potential treatments to counteract these processes.† And the ramifications could be widespread: †If scientists can understand more about how mutations in GBA lead to this alpha-synuclein build-up and eventually PD, they might be able to create new drugs for everyone with the disease, not just those with the mutation (Since everyone with PD experiences alpha-synuclein aggregation).†
This weekís workshop was meant to address the geneís relationship to parkinsonism, how it compares to other genetic risk factors associated to PD such as LRRK2, and possible ways to pharmacologically target GBA.† The major takeaway:† The gene offers exciting potential, but we have a lot more to understand about its role in PD.† Once understood, it could offer an interesting target for potential drug compounds.† Those gathered were also intrigued about how measuring GBA in body fluids could serve as a biomarker for PD.†
In the meantime, MJFF continues to support various research projects into GBA, including one from a team at the University of Washington designed to better understand whatís taking place between a particular mutation in GBA and the development of PD.† Another Foundation awardee, Amicus Therapeutics, is working to develop drugs that increase the activity of an enzyme associated with GBA that doesnít properly function when mutations in the gene occur.† These pre-clinical studies focus on PD; Amicus is also studying their potential in Gaucherís disease. † ††
Stay tuned for updates on our blog, as those in the field of PD research continue to zero in on potential therapies targeting GBA.