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Differential Membrane Binding and Seeding of Distinct $\alpha$-Synuclein Fibrillar Polymorphs

Abstract : The aggregation of the protein $\alpha$-Synuclein ($\alpha$-Syn) leads to different synucleinopathies. We recently showed that structurally distinct fibrillar $\alpha$-Synuclein polymorphs trigger either Parkinson’s Disease or Multiple System Atrophy hallmarks in vivo. Here, we establish structural-molecular basis for these observations. We show that distinct fibrillar $\alpha$-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 $\alpha$ polymorph-dependent and concentration-dependent seeding. We show a polymorph-dependent differential synaptic re-distribution of $\alpha$3-Na$^+$/K$^+$-ATPase, GluA2- AMPA and GluN2B-NMDA receptors but not GluA1-AMPA and mGluR5 receptors. We also demonstrate polymorph-dependent alteration in neuronal network activity upon seeded aggregation of $\alpha$-Syn. Our findings bring new insight into how distinct $\alpha$-Syn polymorphs differentially bind to and seed monomeric $\alpha$-Syn aggregation within neurons, thus affecting neuronal homeostasis through the redistribution of synaptic proteins
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Submitted on : Wednesday, March 11, 2020 - 4:27:01 PM
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Amulya Nidhi Shrivastava, Luc Bousset, Marianne Renner, Virginie Redeker, Jimmy Savistchenko, et al.. Differential Membrane Binding and Seeding of Distinct $\alpha$-Synuclein Fibrillar Polymorphs. Biophysical Journal, Biophysical Society, In press, ⟨10.1016/j.bpj.2020.01.022⟩. ⟨cea-02480815⟩

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