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

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.

Selectivity of Lewy body protein interactions along the aggregation pathway of α-synuclein

“…Examples of such insights are presented below. The importance of these kind of studies has been recently demonstrated by Melki and colleagues 35 who engineered polypeptides to coat the surface of α-SYN fibrils in such a way that their ability to bind to the plasma membrane components and/or their take-up by cell are diminished.…”

Recent Advances in the Study of Na+/K+-ATPase in Neurodegenerative Diseases

“…The α-syn/NKAα3 complex reduced the specific function of NKAα3: rapid Na + extrusion from neurons and eventually resulted in neuronal loss by causing Ca 2+ excitotoxicity ( Figure 3 ) [ 34 ]. These data suggest that designing molecules derived from α-syn binding partners to interfere with α-syn binding to the neuronal plasma membrane, such as NKA-derived polypeptides, holds promise as a disease-modifying therapy for PD [ 80 ].…”