a - synuclein assemblies sequester neuronal a 3 - Na + / K + - ATPase and impair Na + gradient

Extracellular a-synuclein (a-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 a-syn assemblies form clusters within the plasma membrane of neurons. Using a proteomic-based approach, we identify the a3-subunit of Na/K-ATPase (NKA) as a cell surface partner of a-syn assemblies. The interaction strength depended on the state of a-syn, fibrils being the strongest, oligomers weak, and monomers none. Mutations within the neuron-specific a3-subunit are linked to rapid-onset dystonia Parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). We show that freely diffusing a3-NKA are trapped within a-syn clusters resulting in a3-NKA redistribution and formation of larger nanoclusters. This creates regions within the plasma membrane with reduced local densities of a3-NKA, thereby decreasing the efficiency of Na extrusion following stimulus. Thus, interactions of a3-NKA with extracellular a-syn assemblies reduce its pumping activity as its mutations in RDP/AHC.