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

Amulya Nidhi Shrivastava (1) , Luc Bousset (1) , Marianne Renner (2) , Virginie Redeker (1) , Jimmy Savistchenko (1) , Antoine Triller (3) , Ronald Melki (1)

1 LMN - Laboratoire des Maladies Neurodégénératives - UMR 9199
2 Institut du Fer à Moulin
3 IBENS - Institut de biologie de l'ENS Paris

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

Keywords: $\alpha$-Synuclein; protein-protein interaction; membrane protein clustering; seeding; synaptic function

Domains: Life Sciences [q-bio]; Life Sciences [q-bio]; Biochemistry, Molecular Biology; Biochemistry [q-bio.BM]; Life Sciences [q-bio]; Cellular Biology; Cell Behavior [q-bio.CB]; Life Sciences [q-bio]; Neurons and Cognition [q-bio.NC]

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, In press, ⟨10.1016/j.bpj.2020.01.022⟩. ⟨cea-02480815⟩