Study Rationale: In Parkinson’s disease (PD), some of the most common genetic risk factors are changes in the GBA1 gene, which provides instructions to make the enzyme β-glucocerebrosidase (GCase). GCase helps break down waste in cells and depends on another protein, LIMP-2, to be delivered to the right place—the lysosome. If this process fails, waste builds up and can damage brain cells. Understanding how GCase and LIMP-2 work together, especially when GCase is altered by PD-linked mutations, is key to learning more about the disease and the design of novel therapeutic therapies.
Hypothesis: We propose that certain Parkinson’s-associated mutations alter the interaction between GCase and LIMP-2, reducing enzyme function and contributing to disease progression. Understanding these changes will support the development of targeted therapies.
Study Design: We will produce different PD-linked GCase variants in human cell lines and purify these proteins along with LIMP-2. Using advanced cryo-electron microscopy, we will determine the structure of the protein complexes to understand how the mutations change their conformation. We will also test commercial antibodies to simplify and improve the protein purification process. This will help us compare the stability and function of the protein complexes under different conditions.
Impact on Diagnosis/Treatment of Parkinson’s disease: By revealing how GCase mutations affect its function and interaction with LIMP-2, this research may guide the development of new drugs that restore enzyme activity and slow disease progression in GBA1-linked Parkinson’s.
Next Steps for Development: If successful, this study will lay the groundwork for designing targeted therapies and drug screening strategies aimed at stabilizing the GCase-LIMP-2 complex and improving lysosomal function in PD patients.