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Abstract Details

Is GBA1 Neuroprotective in Glia in Slowing Parkinson’s Disease Progression?
Movement Disorders
P7 - Poster Session 7 (11:45 AM-12:45 PM)
3-004
To investigate if restoring GBA1 function in astrocytes can reduce the spread of Lewy pathology in neurons.

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.
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.

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.
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.
Authors/Disclosures
Jeremy R. Weiss
PRESENTER 		Mr. Weiss has nothing to disclose.
Sarah Fish (SIBCR) Sarah Fish has nothing to disclose.
Arnav Khera Mr. Khera has nothing to disclose.
Anna Park (VA Puget Sound Health Care System) Miss Park has nothing to disclose.
Raja E. Estes, BS (VA Puget Sound Health Care System) Ms. Estes has nothing to disclose.
Selina Yu Selina Yu has nothing to disclose.
Leo Pallanck No disclosure on file
Jessica Young (University of Washington) Jessica Young has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Fondation Alzheimer. The institution of Jessica Young has received research support from NIH. Jessica Young has received personal compensation in the range of $500-$4,999 for serving as a Instructor with Aging Alliance.
Marie Y. Davis, MD, PhD (VA Puget Sound) Dr. Davis has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. The institution of Dr. Davis has received research support from NIH NINDS. The institution of Dr. Davis has received research support from University of Washington Institute for Stem Cell and Regenerative Medicine. The institution of Dr. Davis has received research support from VA BLRD. Dr. Davis has received personal compensation in the range of $500-$4,999 for serving as a study section grant reviewer with NIH. Dr. Davis has received personal compensation in the range of $500-$4,999 for serving as a Grant reviewer with Parkinson's Foundation.