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

被引：168

作者：

Shrivastava, Amulya Nidhi ^{[1
]}

Redeker, Virginie ^{[2
]}

Fritz, Nicolas ^{[3
]}

Pieri, Laura ^{[2
]}

Almeida, Leandro G. ^{[1
]}

Spolidoro, Maria ^{[1
]}

Liebmann, Thomas ^{[3
]}

Bousset, Luc ^{[2
]}

Renner, Marianne ^{[1
]}

Lena, Clement ^{[1
]}

Aperia, Anita ^{[3
]}

Melki, Ronald ^{[2
]}

Triller, Antoine ^{[1
]}

机构：

[1] PSL Res Univ, CNRS, Inst Biol ENS IBENS, Ecole Normale Super, Paris, France

[2] CNRS, Paris Saclay Inst Neurosci, Gif Sur Yvette, France

[3] Karolinska Inst, Dept Women & Childrens Hlth, Stockholm, Sweden

来源：

EMBO JOURNAL | 2015年 / 34卷 / 19期

基金：

瑞典研究理事会;

关键词：

misfolding disease; Parkinson's disease; protein aggregation and clustering; single particle tracking; super-resolution imaging; ONSET DYSTONIA-PARKINSONISM; AMYOTROPHIC-LATERAL-SCLEROSIS; DE-NOVO MUTATIONS; ALTERNATING HEMIPLEGIA; TRANSGENIC MICE; SODIUM-PUMP; CELL-DEATH; NA; K-ATPASE; PATHOLOGY; ATP1A3;

D O I：

10.15252/embj.201591397

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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

引用

页码：2408 / 2423

页数：16

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