Objective: Investigate a role for GBA in accelerating the spread of protein aggregates via extracellular vesicles (EVs).

Background: Parkinson’s disease (PD) progression correlates with temporo-spatial distribution of protein aggregates in the brain, suggesting that a mechanism underlying propagation of Lewy pathology can alter the rate of progression of neurodegeneration. Mutations in the gene glucosidase, beta acid 1 (GBA) are not only the most penetrant genetic risk factor for PD and dementia with Lewy bodies^1-5, but also accelerate the progression of symptoms in PD^6-9. Our work and others recently revealed that GBA deficiency causes dysregulation of EVs^12,13, leading us to hypothesize that GBA mutations may accelerate disease progression by promoting the spread of protein aggregates from cell to cell via dysregulated EVs.

Method: Using a previously developed Drosophila model of GBA deficiency (GBA^del) manifesting multiple phenotypes, including neurodegeneration and accelerated protein aggregation¹⁴, we used standard Drosophila reagents, immunohistochemistry and Western blotting to evaluate protein aggregation. We isolated EVs <220 nm in diameter from Drosophila hemolymph per published protocol¹³.

Results: We examined whether tissue specific expression of wildtype GBA could rescue the accelerated protein aggregation present in homozygous GBA^del flies. Expressing wildtype GBA1b in muscle rescued insoluble ubiquitinated protein and Ref(2)p accumulation in brain as well as muscle. Neuronal expression of wildtype dGBA1b also rescued ubiquitinated protein and Ref(2)p aggregation in both brain and muscle. Non-cell autonomous rescue of protein aggregates in brain was also observed with expression of human wildtype GBA in muscle.
EVs isolated from GBA^del flies have increased levels of Ref(2)p and ubiquitinated proteins compared to control flies¹³. Expression of wildtype dGBA1b or human GBA in muscle suppressed increased levels of Ref(2)p and ubiquitinated proteins in GBA^del flies, and human glucocerebrosidase was found in EVs of flies expressing human GBA.

Conclusion: Our results suggest that GBA deficiency mediates PD pathogenesis by accelerating propagation of protein aggregates through dysregulation of EV protein cargo. Elucidating this novel mechanism for GBA will have important implications for disease-modifying treatment of GBA-associated diseases and other aggregate-prone neurodegenerative diseases.

References: 1. Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 2009;361:1651-61. 2. Mata IF, Leverenz JB, Weintraub D, et al. GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson’s disease. Mov Disord 2016;31:95-102. 3. Mata IF, Samii A, Schneer SH, et al. Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol 2008;65:379-82. 4. Tsuang D, Leverenz JB, Lopez OL, et al. GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology. Neurology 2012;79:1944-50. 5. Blauwendraat C, Reed X, Krohn L, et al. Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia. Brain 2020;143:234-48. 6. Davis MY, Johnson CO, Leverenz JB, et al. Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease. JAMA Neurol 2016;73:1217-24. 7. Davis AA, Andruska KM, Benitez BA, Racette BA, Perlmutter JS, Cruchaga C. Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression. Neurobiol Aging 2016;37:209 e1- e7. 8. Brockmann K, Srulijes K, Pflederer S, et al. GBA-associated Parkinson’s disease: reduced survival and more rapid progression in a prospective longitudinal study. Mov Disord 2015;30:407-11. 9. Liu G, Boot B, Locascio JJ, et al. Specifically neuropathic Gaucher’s mutations accelerate cognitive decline in Parkinson’s. Annals of neurology 2016;80:674-85. 10. Stuendl A, Kunadt M, Kruse N, et al. Induction of alpha-synuclein aggregate formation by CSF exosomes from patients with Parkinson’s disease and dementia with Lewy bodies. Brain 2016;139:481-94. 11. Minakaki G, Menges S, Kittel A, et al. Autophagy inhibition promotes SNCA/alpha-synuclein release and transfer via extracellular vesicles with a hybrid autophagosome-exosome-like phenotype. Autophagy 2018;14:98-119. 12. Papadopoulos VE, Nikolopoulou G, Antoniadou I, et al. Modulation of beta-Glucocerebrosidase Increases alpha-Synuclein secretion and Exosome release in Mouse Models of Parkinson’s Disease. Hum Mol Genet 2018. 13. Thomas RE, Vincow ES, Merrihew GE, MacCoss MJ, Davis MY, Pallanck LJ. Glucocerebrosidase deficiency promotes protein aggregation through dysregulation of extracellular vesicles. PLoS Genet 2018;14:e1007694. 14. Davis MY, Trinh K, Thomas RE, et al. Glucocerebrosidase Deficiency in Drosophila Results in alpha-Synuclein-Independent Protein Aggregation and Neurodegeneration. PLoS Genet 2016;12:e1005944.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/glucocerebrosidase-deficiency-mediates-propagation-of-protein-aggregation-via-extracellular-vesicle-dysregulation/