α-synuclein assemblies sequester neuronal α3-Na+/K+-ATPase and impair Na+ gradient

EMBO J. 2015 Oct 1;34(19):2408-23. doi: 10.15252/embj.201591397. Epub 2015 Aug 31.

Abstract

Extracellular α-synuclein (α-syn) assemblies can be up-taken by neurons; however, their interaction with the plasma membrane and proteins has not been studied specifically. Here we demonstrate that α-syn assemblies form clusters within the plasma membrane of neurons. Using a proteomic-based approach, we identify the α3-subunit of Na+/K+-ATPase (NKA) as a cell surface partner of α-syn assemblies. The interaction strength depended on the state of α-syn, fibrils being the strongest, oligomers weak, and monomers none. Mutations within the neuron-specific α3-subunit are linked to rapid-onset dystonia Parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). We show that freely diffusing α3-NKA are trapped within α-syn clusters resulting in α3-NKA redistribution and formation of larger nanoclusters. This creates regions within the plasma membrane with reduced local densities of α3-NKA, thereby decreasing the efficiency of Na+ extrusion following stimulus. Thus, interactions of α3-NKA with extracellular α-syn assemblies reduce its pumping activity as its mutations in RDP/AHC.

Keywords: Parkinson's disease; misfolding disease; protein aggregation and clustering; single particle tracking; super‐resolution imaging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Hemiplegia / genetics
  • Hemiplegia / metabolism*
  • Hemiplegia / pathology
  • Humans
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Mutation*
  • Neurons / metabolism*
  • Neurons / pathology
  • Parkinsonian Disorders / genetics
  • Parkinsonian Disorders / metabolism*
  • Parkinsonian Disorders / pathology
  • Sodium-Potassium-Exchanging ATPase / genetics
  • Sodium-Potassium-Exchanging ATPase / metabolism*
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*

Substances

  • Multiprotein Complexes
  • alpha-Synuclein
  • Sodium-Potassium-Exchanging ATPase
  • sodium potassium ATPase alpha3 subunit, human

Supplementary concepts

  • Alternating hemiplegia of childhood