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Biophys J. 2020 Mar 24;118(6):1301-1320. doi: 10.1016/j.bpj.2020.01.022. Epub 2020 Jan 28.

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

Author information

1
CEA, Institut François Jacob (MIRcen) and CNRS, Laboratory of Neurodegenerative Diseases, Fontenay-aux-Roses, France. Electronic address: amulya.nidhi@gmail.com.
2
CEA, Institut François Jacob (MIRcen) and CNRS, Laboratory of Neurodegenerative Diseases, Fontenay-aux-Roses, France.
3
INSERM, UMR- S 839 Institut du Fer à Moulin, Sorbonne Université, Paris, France.
4
École Normale Supérieure, Institut de Biologie de l'ENS, INSERM, CNRS, PSL, Research University, Paris, France. Electronic address: triller@biologie.ens.fr.
5
CEA, Institut François Jacob (MIRcen) and CNRS, Laboratory of Neurodegenerative Diseases, Fontenay-aux-Roses, France. Electronic address: ronald.melki@cnrs.fr.

Abstract

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 from wild-type mice. We demonstrate a polymorph-dependent and concentration-dependent seeding. We show a polymorph-dependent differential synaptic redistribution of α3-Na+/K+-ATPase, GluA2 subunit containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and GluN2B-subunit containing N-methyl-D-aspartate receptors, but not GluA1 subunit containing α-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 α-Syn. Our findings bring new, to our knowledge, insight into how distinct α-Syn polymorphs differentially bind to and seed monomeric α-Syn aggregation within neurons, thus affecting neuronal homeostasis through the redistribution of synaptic proteins.

PMID:
32059758
PMCID:
PMC7091477
[Available on 2021-03-24]
DOI:
10.1016/j.bpj.2020.01.022
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