Identification and Nanomechanical Characterization of the Fundamental Single-strand Protofilaments of Amyloid α-synuclein Fibrils

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2018 Jun 27

PMID 29941606

Citations 46

Authors

Francesco Simone Ruggeri

Fabrizio Benedetti

Tuomas P J Knowles

Hilal A Lashuel

Sergey Sekatskii

Giovanni Dietler

Affiliations

Soon will be listed here.

Abstract

The formation and spreading of amyloid aggregates from the presynaptic protein α-synuclein in the brain play central roles in the pathogenesis of Parkinson's disease. Here, we use high-resolution atomic force microscopy to investigate the early oligomerization events of α-synuclein with single monomer angstrom resolution. We identify, visualize, and characterize directly the smallest elementary unit in the hierarchical assembly of amyloid fibrils, termed here single-strand protofilaments. We show that protofilaments form from the direct molecular assembly of unfolded monomeric α-synuclein polypeptide chains. To unravel protofilaments' internal structure and elastic properties, we manipulated nanomechanically these species by atomic force spectroscopy. The single-molecule scale identification and characterization of the fundamental unit of amyloid assemblies provide insights into early events underlying their formation and shed light on opportunities for therapeutic intervention at the early stages of aberrant protein self-assembly.

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