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Abstract Details

Glucocerebrosidase Deficiency Mediates Propagation of Protein Aggregation in a Drosophila Model of Neurodegeneration via Modification of Extracellular Vesicles
Movement Disorders
S53 - Movement Disorders: Genetics and Clinical Features (4:03 PM-4:14 PM)
004

Increasing evidence suggests that non-cell autonomous mechanisms contribute to the progression of neurodegenerative diseases such as Parkinson’s disease (PD). Mutations in the gene GBA1 are the strongest genetic risk for factor for developing PD, and also associated with faster disease progression. We used a fly model of GBA1 deficiency that has been previously characterized to have neurodegenerative phenotypes to investigate the role of GBA1 in a novel mechanism involving EVs in accelerating the propagation of pathogenic protein aggregates.

Investigate a potential role for GBA1 deficiency in accelerating the spread of protein aggregates via extracellular vesicles (EVs).

We previously developed a Drosophila model of GBA1 deficiency (GBA1del) that manifests multiple phenotypes, including neurodegeneration and accelerated protein aggregation. We used a novel proteomic method using stable isotope labeling and mass spectrometry to measure global turnover rates and abundances in vivo in GBA1del flies. We used standard Drosophila reagents, immunohistochemistry and Western blotting to evaluate protein aggregation. EV abundance was ascertained by nanoparticle tracking analysis.

Analysis of proteomic data from GBA1del flies revealed that proteins involved in the EV secretory pathway were highly enriched amongst those proteins with significantly increased turnover and abundance. In addition, the increased protein aggregation present in GBA1del fly brains is rescued non-cell autonomously by expression of wildtype dGBA1b in non-neuronal tissues such as muscle and midgut. EVs isolated from GBA1del flies are 6-fold more abundant compared to controls and have elevated EV-associated proteins and ubiquitinated protein aggregates. Knockdown of proteins required for biogenesis of EVs suppressed ubiquitinated protein aggregation in GBA1del fly brains.
Our results suggest that GBA1 deficiency mediates PD pathogenesis by accelerating propagation of protein aggregates through increased EV abundance and altered protein cargo. Elucidating this novel mechanism for GBA1 will have important implications for disease-modifying treatment of GBA1-associated diseases and other aggregate-prone neurodegenerative diseases.
Authors/Disclosures

PRESENTER
No disclosure on file
No disclosure on file
No disclosure on file
Selina Yu Selina Yu has nothing to disclose.
Leo Pallanck No disclosure on file
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.