One of the grand challenges of biophysical chemistry is to understand the principles that govern protein misfolding and aggregation, which is a highly complex process that is sensitive to initial conditions, operates on a huge range of length- and timescales, and has products that range from protein dimers to macroscopic amyloid fibrils. Aberrant aggregation is associated with more than 25 diseases, which include Alzheimer's, Parkinson's, Huntington's, and type II diabetes. Amyloid aggregation has been extensively studied in the test tube, therefore under conditions that are far from physiological relevance. Hence, there is dire need to extend these investigations to in vivo conditions where amyloid formation is affected by a myriad of biochemical interactions. As a hallmark of neurodegenerative diseases, these interactions need to be understood in detail to develop novel therapeutic interventions, as millions of people globally suffer from neurodegenerative disorders and type II diabetes. The aim of this review is to document the progress in the research on amyloid formation from a physicochemical perspective with a special focus on the physiological factors influencing the aggregation of the amyloid-β peptide, the islet amyloid polypeptide, α-synuclein, and the hungingtin protein.

CEITEC Central European Institute of Technology Masaryk University Kamenice 753 5 Brno 625 00 Czech Republic

Department of Biochemistry and Biophysics Stockholm University Svante Arrhenius väg 16C 106 91 Stockholm Sweden

Faculty of Chemistry and Chemical Biology TU Dortmund University Otto Hahn Str 4a 44227 Dortmund Germany

Faculty of Chemistry and Chemical Biology TU Dortmund University Otto Hahn Str 4a 44227 Dortmund Germany and Sanofi Aventis Deutschland GmbH R and D Industriepark Höchst 65926 Frankfurt Germany

Institute of Complex Systems Structural Biochemistry Forschungszentrum Jülich 42525 Jülich Germany and Institute of Theoretical and Computational Chemistry Heinrich Heine University Düsseldorf Universitätsstraße 1 40225 Düsseldorf Germany

Institute of Physical and Theoretical Chemistry TU Braunschweig Rebenring 56 38106 Braunschweig Germany

Institute of Physical and Theoretical Chemistry TU Braunschweig Rebenring 56 38106 Braunschweig Germany and Lead Discovery Wuppertal Bayer AG 42096 Wuppertal Germany

References provided by Crossref.org

Amyloid-β peptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane

Amyloidogenic Intrinsically Disordered Proteins: New Insights into Their Self-Assembly and Their Interaction with Membranes