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Differential Membrane Binding and Seeding of Distinct ?-Synuclein Fibrillar Polymorphs.


ABSTRACT: The aggregation of the protein ?-synuclein (?-Syn) leads to different synucleinopathies. We recently showed that structurally distinct fibrillar ?-Syn polymorphs trigger either Parkinson's disease or multiple system atrophy hallmarks in vivo. Here, we establish a structural-molecular basis for these observations. We show that distinct fibrillar ?-Syn polymorphs bind to and cluster differentially at the plasma membrane in both primary neuronal cultures and organotypic hippocampal slice cultures from wild-type mice. We demonstrate a polymorph-dependent and concentration-dependent seeding. We show a polymorph-dependent differential synaptic redistribution of ?3-Na+/K+-ATPase, GluA2 subunit containing ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and GluN2B-subunit containing N-methyl-D-aspartate receptors, but not GluA1 subunit containing ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and metabotropic glutamate receptor 5 receptors. We also demonstrate polymorph-dependent alteration in neuronal network activity upon seeded aggregation of ?-Syn. Our findings bring new, to our knowledge, insight into how distinct ?-Syn polymorphs differentially bind to and seed monomeric ?-Syn aggregation within neurons, thus affecting neuronal homeostasis through the redistribution of synaptic proteins.

SUBMITTER: Shrivastava AN 

PROVIDER: S-EPMC7091477 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Differential Membrane Binding and Seeding of Distinct α-Synuclein Fibrillar Polymorphs.

Shrivastava Amulya Nidhi AN   Bousset Luc L   Renner Marianne M   Redeker Virginie V   Savistchenko Jimmy J   Triller Antoine A   Melki Ronald R  

Biophysical journal 20200128 6


The aggregation of the protein α-synuclein (α-Syn) leads to different synucleinopathies. We recently showed that structurally distinct fibrillar α-Syn polymorphs trigger either Parkinson's disease or multiple system atrophy hallmarks in vivo. Here, we establish a structural-molecular basis for these observations. We show that distinct fibrillar α-Syn polymorphs bind to and cluster differentially at the plasma membrane in both primary neuronal cultures and organotypic hippocampal slice cultures f  ...[more]

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