Funded Studies
Objective/Rationale:
Mutations in the glucocerebrosidase (GBA) gene are the most common genetic risk factor for Parkinson’s disease (PD). These mutations are present in approximately seven percent of PD patients. The aim of this project is to determine whether the GBA protein (coded by the GBA gene) is altered in the majority brains of sporadic (cause unknown) PD patients without these mutations. These data will guide the therapeutic development of GBA-targeted therapies for PD.
Project Description:
Brains from sporadic PD patients without GBA gene mutations will be compared to two groups: aged controls and PD patients with GBA mutations. Two key aspects — GBA protein levels and its enzymatic activity — will be analyzed. If the GBA protein is altered, further experiments will be undertaken to understand the mechanism of these changes. In addition, the relationship between levels in cerebrospinal fluid and in the brain will be tested.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Understanding the changes in the GBA protein and their mechanisms will allow for development of targeted therapies for PD patients. Experiments in cerebrospinal fluid may enable targeting therapies towards subpopulations of PD patients with changes in GBA who would be most likely to benefit.
Anticipated Outcome:
Demonstrating changes in GBA will provide a strong rationale for development of GBA-targeted therapies for sporadic PD patients. Understanding of the underlying mechanism responsible for these changes will allow generation of more predictive cell and pre-clinical models, as well as development of therapies targeted at this specific mechanism.
Final Outcome
Mutations in the glucocerebrosidase (GBA) gene represent the most common genetic risk factor for Parkinson's disease (PD) and other synucleinopathies. Many of these mutations lead to decreased enzymatic activity/stability and have been shown to impair lysosomal functionality, including clearance of alpha-synuclein. The objective was to determine whether there is a decrease in GBA activity/levels in sporadic PD. We measured a significant decrease in GBA enzymatic activity and protein levels in multiple brain regions from sporadic PD compared to controls. GBA mutation carriers had a further reduction in GBA activity compared to controls. We measured a significant increase in alpha-synuclein, which correlates with the decreased GBA activity.
In conclusion, these data demonstrate a significant reduction in the levels and activity of GBA in PD cases, both with and without GBA mutations, providing genetic and biochemical data as a foundation for potential drug discovery programs seeking to enhance GBA activity.
Presentations & Publications
W. Shan, Y. Chen, P. Buckett, P. Loos, H. Samaroo, Z. Berger, C. Oborski, S. Paciga, C.H. Adler, T.P. Beach, G.Serrano, D. Volfson, A. Winslow, W.D. Hirst (2014) Assessing glucocerebrosidase in sporadic Parkinson's disease - is GBA a valid target for sporadic Parkinson's disease? Invited poster presentation: Michael J Fox Foundation's 8th Annual Parkinson's Disease Therapeutics Conference, New York City, October 29th 2014.
Warren D Hirst, Weisong Shan, Yi Chen, Peter D. Buckett, Paula Loos, Harry Samaroo, Zdenek Berger, Christine Oborski, Sara Paciga, Charles H Adler, Thomas P Beach, Geidy Serrano, Dmitri Volfson, Ashley Winslow. Glucocerebrosidase (GBA) levels and activity are reduced in sporadic Parkinson's disease. Selected for oral presentation. AD/PD 2015 Conference, Nice, France, March 18-22nd 2015.
March 2015