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

Date Published: July 15, 2017

Publisher: Impact Journals LLC

Author(s): 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.


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.

Partial Text

Aging is the most prominent risk factor for a wide variety of neurodegenerative diseases. A common feature of these age-related diseases is protein misfolding and aggregation of toxic peptides due to age-related decline of cellular functions including protein sorting and degradation mechanisms. Parkinson’s disease (PD), the second most common neurodegene-rative disorder, is characterized primarily by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). This neurodegeneration is accompanied by motor symptoms including tremor, bradykinesia, rigidity and postural instability. The major neuropathological hallmarks of PD are intraneuronal accumulations of misfolded protein, which are termed Lewy bodies (LB) and Lewy neurites (LN). The main component of LBs and LNs is aggregated alpha-synuclein (α-syn) [1]. Recent studies identified oligomeric intermediates of α-syn aggregates to be the predominantly neurotoxic species. Besides their toxic properties in cell culture experiments [12], α-syn oligomers are able to induce Parkinson-like symptoms in animal models [13]. Several factors, including oxidative stress [14], pH and temperature [10], post-translational modifications [15, 16], proteolysis [17, 18] and high concentrations of fatty acids [19–21], phospholipids and metal ions [14, 22, 23], were shown to induce and/or modulate α-syn structure and oligomerization in vitro. Emerging evidence suggests that α-syn oligomers spread from cell-to-cell and encourage the propagation of neurodegeneration in a prion-like manner [26]. In line with this, α-syn oligomers were found in conditioned media from cell cultures as well as human CSF and plasma [27–30]. It has been demonstrated that α-syn can be secreted from neuronal cells, enter other neighboring cells, and seed small intracellular aggregates [31]. We and others have shown that α-syn oligomers can be secreted in association with exosomes [32–35].

The current consensus on how α-syn contributes to the development of Parkinson’s disease includes misfolding of the protein, aggregation into toxic species, spreading of these toxic species throughout the brain and seeding of aggregation in a prion-like manner. Since oligomeric intermediates have been identified to be the neurotoxic species, research has focused on the mechanisms and transport pathways involved in the assembly and secretion of α-syn oligomers. Besides the fact that α-syn itself was found to participate in vesicle transport at endosomal and Golgi compartments [78], recent publications identified mutations in VPS35 in familial PD [38–41]. Here, we provide evidence that the GGA protein family contributes to the aggregation and secretion of α-syn oligomers.




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