Is GBA1 Neuroprotective in Glia in Slowing Parkinson’s Disease Progression?
Jeremy Weiss1, Sarah Fish3, Arnav Khera1, Anna Park2, Raja Estes4, Selina Yu1, Leo Pallanck5, Jessica Young6, Marie Davis7
1Neurology, Veterans Affairs Puget Sound, 2Veterans Affairs Puget Sound, 3SIBCR, 4VA Puget Sound Health Care System, 5University of Washington, 6Pathology, University of Washington, 7VA Puget Sound
Objective:
To investigate if restoring GBA1 function in astrocytes can reduce the spread of Lewy pathology in neurons.
Background:
Mutations in the gene glucosidase, beta acid 1 (GBA1) are the strongest genetic risk factor for Parkinson's Disease (PD) and accelerate disease progression. Our work using a Drosophila GBA1 deficient model revealed altered exosomes may act as vehicles to accelerate protein aggregate spread. Restoring wildtype glucocerebrosidase activity in glia reduced protein aggregation in brain.
Design/Methods:
We developed a Drosophila model of GBA1 deficiency (GBAdel) by deleting the Drosophila homolog of GBA1, dGBA1b. Human induced pluripotent stem cells (iPSCs) were generated from an individual with PD carrying the IVS2+1G>A GBA mutation (GBAIVS PD). Neurons and astrocytes were differentiated from GBAIVS PD, isogenic GBAWT PD, and age- and sex-matched healthy control iPSCs using StemCell Technologies reagents and protocols. Confirmation for differentiation was performed by IHC. Neuronal EVs were isolated by size exclusion chromatography from conditioned media. Co-culture of iPSC-neurons and astrocytes were performed using TransWell plates.
Results:
Expression of wildtype dGBA1b in flight muscle or glia of GBAdel mutant flies rescued protein aggregation in the brain, and also rescued levels of exosomal Rab11, Rab 7 and Ref(2)p. GBAIVS PD dopaminergic neurons were found to have larger early endosome and lysosome compartments compared to controls. GBAIVS PD astrocytes also had enlarged early endosomes but no significant increase in volume of autophagolysosomes compared to controls.
Conclusions:
Our Drosophila model supports the hypothesis that GBA1 deficiency alters endolysosomal trafficking, influencing exosome biogenesis, which may accelerate the spread of Lewy pathology. Our iPSC-cell culture work suggests GBA1 deficiency has differential effects on different cell types. We are now examining whether wildtype GBA1 function in astrocytes can slow Lewy pathology propagation. This could elucidate mechanisms to halt or slow down the spread of pathogenic protein aggregation in PD.