The Golgi-localized, gamma ear-containing, ARF-binding (GGA) protein family alters alpha synuclein (α-syn) oligomerization and secretion.

Abstract

Several age-related neurodegenerative disorders are associated with protein misfolding and aggregation of toxic peptides. α-synuclein (α-syn) aggregation and the resulting cytotoxicity is a hallmark of Parkinson's disease (PD) as well as dementia with Lewy bodies. Rising evidence points to oligomeric and pre-fibrillar forms as the pathogenic species, and oligomer secretion seems to be crucial for the spreading and progression of PD pathology. Recent studies implicate that dysfunctions in endolysosomal/autophagosomal pathways increase α-syn secretion. Mutation in the retromer-complex protein VPS35, which is involved in endosome to Golgi transport, was suggested to cause familial PD. GGA proteins regulate vesicular traffic between Golgi and endosomes and might work as antagonists for retromer complex mediated transport. To investigate the role of the GGAs in the α-syn oligomerization and/or secretion process we utilized protein-fragment complementation assays (PCA). We here demonstrate that GGAs alter α-syn oligomer secretion and α-syn oligomer-mediated toxicity. Specifically, we determined that GGA3 modifies extracellular α-syn species in an exosome-independent manner. Our data suggest that GGA3 drives α-syn oligomerization in endosomal compartments and thus facilitates α-syn oligomer secretion. Preventing the early events in α-syn oligomer release may be a novel approach to halt disease spreading in PD and other synucleinopathies.

• Authors: Bjoern von Einem, Judith Eschbach, Martin Kiechle, Anke Wahler, Dietmar R Thal, Pamela J McLean, Jochen H Weishaupt, Albert C Ludolph, Christine A F von Arnim, Karin M Danzer
• Journal: Aging (Aging (Albany NY)) Vol. 9 Issue 7 Pg. 1677-1697 (07 15 2017) ISSN: 1945-4589 [Electronic] United States
• PMID: 28722658 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Vesicular Transport
• GGA adaptor proteins
• alpha-Synuclein

Topics

• Adaptor Proteins, Vesicular Transport (genetics, metabolism)
• Animals
• Cell Line
• Cerebellum
• Gene Expression Regulation (physiology)
• Golgi Apparatus (metabolism)
• Humans
• Mice
• Multigene Family
• Parkinson Disease (metabolism)
• Substantia Nigra (cytology)
• alpha-Synuclein (genetics, metabolism)