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Abstract Details

Glucocerebrosidase Deficiency Mediates Propagation of Protein Aggregation in Neurodegeneration via Modification of Extracellular Vesicles
Movement Disorders
S36 - Movement Disorders: Clinical and Pathologic Characterization of Neurodegenerative Movement Disorders (2:00 PM-2:12 PM)
006
Mutations in the gene glucosidase, beta acid 1 (GBA) are not only the most penetrant genetic risk factor for PD, but also accelerate the progression of PD. Our prior work revealed that mutations in GBA alter extracellular vesicles (EVs), promoting the spread of protein aggregation from cell to cell. We hypothesize that GBA mutations accelerate disease progression by promoting propagation of Lewy pathology from cell to cell via EVs. 
To investigate why GBA mutations are associated with faster progression of Parkinson’s disease (PD).  
We have developed a Drosophila model of GBA deficiency (GBAdel) manifesting neurodegeneration and accelerated protein aggregation. We also developed a human neuronal model by generating human induced pluripotent stem cells (iPSCs) from an individual with PD carrying the IVS2+1G>A GBA mutation (GBAIVS PD). Neurons were differentiated from GBAIVS PD iPSCs, isogenic GBAWT PD iPSCs, and iPSCs from an age- and sex-matched healthy control. Immunocytochemistry and western blot were used to evaluate protein aggregation. EVs were isolated by size exclusion chromatography and analyzed by ZetaView nanoparticle analyzer. 
Expression of wildtype dGBA1b in muscle of GBAdel mutant flies rescued protein aggregation in brain. This non-cell autonomous rescue was accompanied by normalization of alterations observed in EVs from GBAdelflies. Similarly, human GBAIVS PD neurons have increased ubiquitinated proteins. EVs from GBAIVS PD neurons have increased ubiquitinated proteins compared to EVs from GBAWT PD or healthy control neurons. 
Our results suggest that GBA deficiency mediates PD pathogenesis by accelerating propagation of pathogenic protein aggregation through alteration of EV protein cargo. We are investigating how GBA influences endolysosomal trafficking and EV biogenesis and will test whether GBAIVS PD EVs can propagate protein aggregation faster in recipient neurons than control EVs. Understanding mechanisms regulating the spread of protein aggregates could reveal novel therapeutic targets to slow the rate of progression of neurodegeneration.
Authors/Disclosures
Marie Davis (VA Puget Sound)
PRESENTER
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.
Arnav Khera Mr. Khera has nothing to disclose.
No disclosure on file
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Raja Estes (VA Puget Sound Health Care System) Ms. Estes has nothing to disclose.
No disclosure on file
No disclosure on file