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

Elodie Monsellier,Maya Bendifallah,Ronald Melki,Virginie Redeker

doi:10.1371/journal.pone.0237328

Abstract

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 polypeptides 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.

Highlights

The aggregation of proteins into fibrillar high molecular-weight species is involved in human degenerative diseases, including Alzheimer’s, Parkinson’s, or Huntington’s [1]
Hsc70 alone remains in the supernatant, whereas it is pulled into the pellet when incubated for 1h at room temperature with pre-formed αSyn fibrils
Unlabeled Hsc70 competed in a dose-dependent way with the binding of labeled Hsc70 to αSyn fibrils (Fig 1C), and the KD between Hsc70 and αSyn fibrils was identical to the KD between Hsc70-ATTO488 and αSyn fibrils (0.45 ± 0.08 μM)

Summary

Introduction

The aggregation of proteins into fibrillar high molecular-weight species is involved in human degenerative diseases, including Alzheimer’s, Parkinson’s, or Huntington’s [1]. It has become evident that those protein aggregates traffic between neuronal cells and amplify by seeding the aggregation of their constituting proteins [2,3,4,5]. This prion-like phenomenon is thought to be responsible for the stereotypic progression of the pathology in the brain [2,5]. The extracellular aggregates dock next to the membrane of naïve neuronal cells [13,14] This membrane binding steps is followed by the internalization of the fibrils, mainly through endocytosis [15,16]. Once in the cells the aggregates reach the cytoplasm, where they recruit the otherwise soluble endogenous protein they are made of [17], after compromising endo-lysosomal integrity [18]

Methods

Results

Conclusion