α-synuclein assemblies sequester neuronal α3-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.
École Normale Supérieure, Institut de Biologie de l'ENS (IBENS) INSERM CNRS PSL Research University, Paris, France.
Amulya Nidhi
AN
Shrivastava
Paris-Saclay Institute of Neuroscience CNRS, Gif-sur-Yvette, France.
Virginie
V
Redeker
Department of Women and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Nicolas
N
Fritz
Paris-Saclay Institute of Neuroscience CNRS, Gif-sur-Yvette, France.
Laura
L
Pieri
École Normale Supérieure, Institut de Biologie de l'ENS (IBENS) INSERM CNRS PSL Research University, Paris, France.
Leandro G
LG
Almeida
École Normale Supérieure, Institut de Biologie de l'ENS (IBENS) INSERM CNRS PSL Research University, Paris, France.
Maria
M
Spolidoro
Department of Women and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Thomas
T
Liebmann
Paris-Saclay Institute of Neuroscience CNRS, Gif-sur-Yvette, France.
Luc
L
Bousset
École Normale Supérieure, Institut de Biologie de l'ENS (IBENS) INSERM CNRS PSL Research University, Paris, France.
Marianne
M
Renner
École Normale Supérieure, Institut de Biologie de l'ENS (IBENS) INSERM CNRS PSL Research University, Paris, France.
Clément
C
Léna
Department of Women and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Anita
A
Aperia
Paris-Saclay Institute of Neuroscience CNRS, Gif-sur-Yvette, France ronald.melki@lebs.cnrs-gif.fr triller@biologie.ens.fr.
Ronald
R
Melki
École Normale Supérieure, Institut de Biologie de l'ENS (IBENS) INSERM CNRS PSL Research University, Paris, France ronald.melki@lebs.cnrs-gif.fr triller@biologie.ens.fr.
Antoine
A
Triller
D006429:Hemiplegia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D046912:Multiprotein Complexes; D000254:Sodium-Potassium-Exchanging ATPase; D051844:alpha-Synuclein; C488756:ATP1A3 protein, human
Parkinson's disease; misfolding disease; protein aggregation and clustering; single particle tracking; super‐resolution imaging