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

ABSTRACT: Extracellular ?-synuclein (?-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 ?-syn assemblies form clusters within the plasma membrane of neurons. Using a proteomic-based approach, we identify the ?3-subunit of Na+/K+-ATPase (NKA) as a cell surface partner of ?-syn assemblies. The interaction strength depended on the state of ?-syn, fibrils being the strongest, oligomers weak, and monomers none. Mutations within the neuron-specific ?3-subunit are linked to rapid-onset dystonia Parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). We show that freely diffusing ?3-NKA are trapped within ?-syn clusters resulting in ?3-NKA redistribution and formation of larger nanoclusters. This creates regions within the plasma membrane with reduced local densities of ?3-NKA, thereby decreasing the efficiency of Na+ extrusion following stimulus. Thus, interactions of ?3-NKA with extracellular ?-syn assemblies reduce its pumping activity as its mutations in RDP/AHC.

SUBMITTER: Shrivastava AN

PROVIDER: S-EPMC4601662 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Shrivastava Amulya Nidhi AN Redeker Virginie V Fritz Nicolas N Pieri Laura L Almeida Leandro G LG Spolidoro Maria M Liebmann Thomas T Bousset Luc L Renner Marianne M Léna Clément C Aperia Anita A Melki Ronald R Triller Antoine A

The EMBO journal 20150831 19

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, ...[more]

PMID: 26323479

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Project description:The whole-cell voltage-clamp technique was used in rat cardiac myocytes to investigate the kinetics of ADP binding to phosphorylated states of Na,K-ATPase and its effects on presteady-state Na(+)-dependent charge movements by this enzyme. Ouabain-sensitive transient currents generated by Na,K-ATPase functioning in electroneutral Na(+)-Na(+) exchange mode were measured at 23 degrees C with pipette ADP concentrations ([ADP]) of up to 4.3 mM and extracellular Na(+) concentrations ([Na](o)) between 36 and 145 mM at membrane potentials (V(M)) from -160 to +80 mV. Analysis of charge-V(M) curves showed that the midpoint potential of charge distribution was shifted toward more positive V(M) both by increasing [ADP] at constant Na(+)(o) and by increasing [Na](o) at constant ADP. The total quantity of mobile charge, on the other hand, was found to be independent of changes in [ADP] or [Na](o). The presence of ADP increased the apparent rate constant for current relaxation at hyperpolarizing V(M) but decreased it at depolarizing V(M) as compared to control (no added ADP), an indication that ADP binding facilitates backward reaction steps during Na(+)-Na(+) exchange while slowing forward reactions. Data analysis using a pseudo three-state model yielded an apparent K(d) of approximately 6 mM for ADP binding to and release from the Na,K-ATPase phosphoenzyme; a value of 130 s(-1) for k(2), a rate constant that groups Na(+) deocclusion/release and the enzyme conformational transition E(1) approximately P --> E(2)-P; a value of 162 s(-1)M(-1) for k(-2), a lumped second-order V(M)-independent rate constant describing the reverse reactions; and a Hill coefficient of approximately 1 for Na(+)(o) binding to E(2)-P. The results are consistent with electroneutral release of ADP before Na(+) is deoccluded and released through an ion well. The same approach can be used to study additional charge-moving reactions and associated electrically silent steps of the Na,K-pump and other transporters.

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

Publications

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

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