Polypeptides derived from α-Synuclein binding partners to prevent α-Synuclein fibrils interaction with and take-up by cells

Elodie Monsellier (1) , Maya Bendifallah (1) , Virginie Redeker (1) , Ronald Melki (1)

1 LMN - Laboratoire des Maladies Neurodégénératives - UMR 9199

α-Synuclein (αSyn) fibrils spread from one neuronal cell to another. This prion-like phenomenon is believed to contribute to the progression of the pathology in Parkinson's disease and other synucleinopathies. The binding of αSyn fibrils originating from affected cells to the plasma membrane of naïve cells is key in their prion-like propagation propensity. To interfere with this process, we designed polypeptides derived from proteins we previously showed to interact with αSyn fibrils, namely the molecular chaperone Hsc70 and the sodium/potassium pump NaK-ATPase and assessed their capacity to bind αSyn fibrils and/ or interfere with their take-up by cells of neuronal origin. We demonstrate here that polypep-tides that coat αSyn fibrils surfaces in such a way that they are changed affect αSyn fibrils binding to the plasma membrane components and/or their take-up by cells. Altogether our observations suggest that the rationale design of αSyn fibrils polypeptide binders that interfere with their propagation between neuronal cells holds therapeutic potential.

Domains: Biochemistry [q-bio.BM]; Structural Biology [q-bio.BM]; Neurons and Cognition [q-bio.NC]; Cellular Biology; Molecular biology

Elodie Monsellier, Maya Bendifallah, Virginie Redeker, Ronald Melki. Polypeptides derived from α-Synuclein binding partners to prevent α-Synuclein fibrils interaction with and take-up by cells. PLoS ONE, 2020, ⟨10.1371/journal.pone.0237328⟩. ⟨cea-02915659⟩