Understanding how GBA mutations influence Parkinson’s disease progression (S42.003)

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Objective: To investigate mechanisms underlying the clinical observation that GBA mutations are associated with increased risk of developing PD, along with faster progression of motor and cognitive symptoms. Background: Mutations in the gene glucosidase, beta acid 1 (GBA) are the strongest genetic risk factor for Parkinson’s Disease (PD) and accelerate disease progression. Our work using a Drosophila GBA deficient model revealed altered exosomes may act as vehicles to accelerate protein aggregate spread. We are further investigating how GBA affects neuronal endolysosomal trafficking and exosome biogenesis. Design/Methods: We developed a Drosophila model of GBA deficiency (GBAdel) by deleting the Drosophila homolog of GBA. Human induced pluripotent stem cells (iPSCs) were generated from an individual with PD carrying the IVS2+1G>A GBA mutation (GBAIVS PD). Neurons 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 are isolated by size exclusion chromatography from conditioned media. Results: Exosomes isolated from GBAdel mutant flies have altered protein cargo, including increased levels of exosome-intrinsic proteins Rab11 and Rab7, and increased oligomerized Ref(2)p, the Drosophila ortholog for p62. 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. Conclusions: Our Drosophila model supports the hypothesis that GBA deficiency alters exosomes, which may act as a vehicle to accelerate the spread of Lewy pathology. We are now examining how GBA alters endolysosomal trafficking leading to exosome biogenesis in our iPSC model, and how altered exosomes can be a vehicle for Lewy pathology propagation. This could elucidate mechanisms to halt or slow down the spread of pathogenic protein aggregation in PD. Disclosure: Mr. Khera has nothing to disclose. Ms. Fish has nothing to disclose. Ms. Estes has nothing to disclose. Selina Yu has nothing to disclose. Leo Pallanck has nothing to disclose. The institution of Dr. Young has received research support from NIH. The institution of Dr. Young has received research support from BrightFocus Foundation. The institution of Dr. Young has received research support from 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.

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