December 31, 2025

@michaelokun

Can we salvage GCase to develop better treatments for Parkinson’s and especially GBA1 genetic related Parkinson's? Glucocerebrosidase (GCASE) is a lysosomal enzyme that helps cells recycle certain fats, and when it does not work properly, it raises the risk for Parkinson’s disease. Henderson and colleagues describe in a new paper in Movement Disorders how small molecule therapies are being developed to rescue glucocerebrosidase function in GBA1 associated Parkinsonism. Key Points: - GBA1 variants reduce glucocerebrosidase activity and disrupt lysosomal health which increases Parkinson’s risk. - Small molecules fall into distinct classes including activators, chaperones and proteostasis regulators and they work in very different ways. - Matching the right mechanism to the right biology is likely essential for future trials to succeed. My take: This paper brings much needed clarity to a crowded and sometimes confusing space. Precision matters here. Not all GCase drugs are created equal and understanding how they work may determine whether this strategy truly changes the Parkinson’s trajectory. I also enjoyed interviewing Ellen Sidransky for our new book www.pdplan.org Here are 5 points that resonated w/ me: 1- GBA1 related Parkinson’s is one of the clearest examples of a genetically informed drug target in the disease. 2- Helping the enzyme fold, traffic or work better may be more important than simply lowering toxic lipids. 3- Some drugs increase enzyme activity, while others help it reach the lysosome where it belongs. 4- Prior trial failures teach us that biology matters more than good intentions. 5- Getting this right could help not only folks w GBA1 variants, but possibly a broader Parkinson’s population. https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.70168 #michaelokun #fixelinstitute #parkinson