{alpha}-synuclein assemblies sequester neuronal {alpha}3-Na+/K+-ATPase and impair Na+ gradient

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.

Source: EMBO Journal - September 30, 2015 Category: Molecular Biology Authors: Shrivastava, A. N., Redeker, V., Fritz, N., Pieri, L., Almeida, L. G., Spolidoro, M., Liebmann, T., Bousset, L., Renner, M., Lena, C., Aperia, A., Melki, R., Triller, A. Tags: Neuroscience Articles Source Type: research