Abstract Details

Title Glucocerebrosidase Deficiency Mediates Propagation of Protein Aggregation in Neurodegeneration via Modification of Extracellular Vesicles

Topic Movement Disorders

Presentation(s) S36 - Movement Disorders: Clinical and Pathologic Characterization of Neurodegenerative Movement Disorders (2:00 PM-2:12 PM)

Poster/Presentation
Number 006

Background 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.

Objective To investigate why GBA mutations are associated with faster progression of Parkinson’s disease (PD).

Design/Methods We have developed a Drosophila model of GBA deficiency (GBA^del) 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 (GBA^IVS PD). Neurons were differentiated from GBA^IVS PD iPSCs, isogenic GBA^WT 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.

Results Expression of wildtype dGBA1b in muscle of GBA^del mutant flies rescued protein aggregation in brain. This non-cell autonomous rescue was accompanied by normalization of alterations observed in EVs from GBA^delflies. Similarly, human GBA^IVS PD neurons have increased ubiquitinated proteins. EVs from GBA^IVS PD neurons have increased ubiquitinated proteins compared to EVs from GBA^WT PD or healthy control neurons.

Conclusions 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 GBA^IVS 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 Y. Davis, MD, PhD (VA Puget Sound) PRESENTER	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.
Arnav Khera	Mr. Khera has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Selina Yu	No disclosure on file
Raja E. Estes, BS (VA Puget Sound Health Care System)	Ms. Estes has nothing to disclose.
Leo Pallanck	No disclosure on file
Jessica Young (University of Washington)	No disclosure on file