Investigating a neuroprotective role of GBA in astrocytes

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A key feature of Parkinson’s disease (PD) is abnormal protein aggregation within neurons in the brain. These neuronal protein aggregates spread throughout the nervous system as PD progresses, but how this occurs remains unclear. Recent work suggests that astrocytes, which support neuronal function by providing energy and protection from cellular stressors, may also have a neuroprotective role in PD and other neurodegenerative diseases. This proposal investigates a potential new role for the gene GBA, a common genetic risk factor for PD that is also associated with faster disease progression. While most studies of GBA focus exclusively on its role in neurons, we will test whether GBA is required in astrocytes to uptake and degrade neuronal-derived proteins in the extracellular matrix to reduce propagation of pathogenic neuronal protein aggregates. Our recent work using our Drosophila GBA deficient model (GBAdel) of PD indicates that exosomes are an important vehicle mediating the spread of protein aggregation. GBA deficiency dysregulates exosome formation, fusion, and/or content. Surprisingly, we found that glial expression of wildtype GBA can reduce protein aggregation present in GBAdel fly brains. To further investigate a possible neuroprotective role for GBA in astrocytes, we will use cultured neurons and astrocytes differentiated from human induced pluripotent stem cells generated from PD patients carrying GBA mutations. Unrelated healthy age- and sex-matched control and isogenic controls generated by CRISPR/Cas9 reversion of the GBA mutation to wildtype will be used as controls. We will first determine whether GBA is important for astrocyte uptake and processing of neuronal-derived EVs by examining GBA PD versus control astrocyte uptake and intracellular trafficking of neuronal EVs containing synuclein-GFP fusion protein. We will then test whether GBA has a neuroprotective role in astrocytes by co- culturing GBA PD or control astrocytes with GBA PD or control neurons and examine protein aggregation, endolysosomal trafficking and cell survival in both cell types. The results from this study could uncover new therapeutic targets to enhance the neuroprotective function of astrocytes, leading to treatments that could slow or halt the progression of PD and other neurodegenerative diseases characterized by protein aggregates.