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

Amulya Nidhi Shrivastava, Virginie Redeker, Nicolas Fritz, Laura Pieri, Leandro G Almeida, Maria Spolidoro, Thomas Liebmann, Luc Bousset, Marianne Renner, Clément Léna, Anita Aperia, Ronald Melki, Antoine Triller

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.