α-synuclein assemblies sequester neuronal α3-Na+/K+-ATPase and impair Na+ gradient
Amulya Nidhi Shrivastava1, Virginie Redeker2, Nicolas Fritz3
1École Normale Supérieure, Institut de Biologie de l'ENS (IBENS) INSERM CNRS PSL Research University, Paris, France.
The EMBO Journal
|September 2, 2015
Summary
Extracellular alpha-synuclein (α-syn) assemblies interact with neuronal membranes, forming clusters that trap the α3-subunit of Na+/K+-ATPase (NKA). This interaction impairs NKA
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Extracellular alpha-synuclein (α-syn) assemblies are implicated in neurodegenerative diseases.
- The specific interactions of α-syn assemblies with neuronal plasma membranes and surface proteins remain largely uncharacterized.
Purpose of the Study:
- To investigate the interaction of extracellular α-synuclein assemblies with the neuronal plasma membrane.
- To identify specific cell surface proteins that interact with α-synuclein assemblies.
- To elucidate the functional consequences of these interactions on neuronal physiology.
Main Methods:
- Proteomic-based approach to identify interacting proteins.
- Advanced microscopy techniques to visualize α-synuclein assembly-membrane interactions.
- Biochemical assays to assess Na+/K+-ATPase activity.
Main Results:
- α-synuclein assemblies form clusters within the neuronal plasma membrane.
- The α3-subunit of Na+/K+-ATPase (NKA) was identified as a specific binding partner for α-synuclein assemblies.
- Interaction strength varied with α-synuclein state: fibrils > oligomers > monomers.
- α-synuclein clustering leads to α3-NKA trapping, redistribution, and reduced Na+ extrusion efficiency.
- Mutations in α3-NKA are linked to neurological disorders like RDP and AHC.
Conclusions:
- Extracellular α-synuclein assemblies directly interact with and alter the organization of α3-NKA at the neuronal surface.
- This interaction impairs the critical Na+ pumping function of NKA, potentially contributing to the pathogenesis of neurological conditions associated with α3-NKA mutations.
Keywords:
Parkinson's diseasemisfolding diseaseprotein aggregation and clusteringsingle particle trackingsuper‐resolution imagingMore Related Videos
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