Nanomechanics of Neurotoxic Proteins: Insights at the Start of the Neurodegeneration Cascade

Abstract

Amyloidogenic neurodegenerative diseases are one of the most widely investigated groups of human disorders. In the last three decades the understanding of the molecular pathogenesis of this group of disorders has experienced remarkable progress, including the discoveries of the causative genes and proteins involved in Alzheimer's, Parkinson's or Huntington's diseases. The causative link between these so-called 'neurotoxic' proteins, a subset of the class of intrinsically disordered proteins (IDPs), and the development of disease has been well established. However, critical questions of neurodegeneration, such as the nature of the specific neurotoxic conformation, and why different neurons degenerate in different diseases, remain unsolved. In recent years, emerging single-molecule techniques have been used to study single molecules of neurotoxic proteins and to make direct measurements of their conformational polymorphism and fast fluctuations. This chapter aims to provide an overall view of the specific contributions of one of these techniques - single-molecule force spectroscopy - that allows the manipulation and analysis (nanomechanics) of single molecules. These studies on neurotoxic protein nanomechanics have shed light on the nature and behavior of these proteins whose associated diseases have such a high social and health impact. We also indicate the key open questions in this field; the answers to these questions will provide a more complete molecular understanding of neurodegeneration.