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Recombinant α- β- and γ-Synucleins Stimulate Protein Phosphatase 2A Catalytic Subunit Activity in Cell Free Assays
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The Golgi-localized, gamma ear-containing, ARF-binding (GGA) protein family alters alpha synuclein (α-syn)

Bjoern von Einem1, Judith Eschbach1, Martin Kiechle1

  • 1Department of Neurology, Ulm University, Ulm 89081, Germany.

Aging
|July 20, 2017
PubMed

Insights

GGA proteins, particularly GGA3, promote the secretion of toxic alpha-synuclein (α-syn) oligomers, driving Parkinson's disease (PD) pathology. Targeting GGA3 may offer a new strategy to inhibit α-syn spread in synucleinopathies.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Protein misfolding and aggregation, particularly of alpha-synuclein (α-syn), are central to neurodegenerative diseases like Parkinson's disease (PD).
  • Oligomeric forms of α-syn are considered the primary pathogenic species, and their extracellular secretion is critical for disease progression.
  • Dysfunctions in endolysosomal pathways and mutations in proteins like VPS35 are linked to familial PD and α-syn secretion.

Purpose of the Study:

  • To investigate the role of GGA proteins in α-syn oligomerization and secretion.
  • To determine if GGA proteins influence the toxicity of secreted α-syn oligomers.
  • To explore potential therapeutic strategies targeting α-syn secretion in PD.

Main Methods:

  • Utilized protein-fragment complementation assays (PCA) to study α-syn oligomerization and secretion.
  • Investigated the effect of GGA proteins on extracellular α-syn species.
  • Assessed the impact of GGA3 on α-syn oligomer-mediated toxicity.

Main Results:

  • GGA proteins were found to alter α-syn oligomer secretion and associated toxicity.
  • GGA3 specifically modifies extracellular α-syn species in an exosome-independent manner.
  • Data suggest GGA3 promotes α-syn oligomerization within endosomal compartments, facilitating its secretion.

Conclusions:

  • GGA3 plays a significant role in driving α-syn oligomerization and secretion.
  • Targeting early α-syn oligomer release mechanisms, potentially involving GGA3, could be a novel therapeutic approach for PD and other synucleinopathies.
Keywords:
ARF-binding (GGA)Parkinson's disease (PD)gamma ear-containinggolgi-localizedoligomerssecretiontransportα-synuclein (α-syn)

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