Chemical Strategies for Controlling Protein Folding and Elucidating the Molecular Mechanisms of Amyloid Formation and Toxicity

Abstract

It has been more than a century since the first evidence linking the process of amyloid formation to the pathogenesis of Alzheimer's disease. During the last three decades in particular, increasing evidence from various sources (pathology, genetics, cell culture studies, biochemistry, and biophysics) continues to point to a central role for the pathogenesis of several incurable neurodegenerative and systemic diseases. This is in part driven by our improved understanding of the molecular mechanisms of protein misfolding and aggregation and the structural properties of the different aggregates in the amyloid pathway and the emergence of new tools and experimental approaches that permit better characterization of amyloid formation in vivo. Despite these advances, detailed mechanistic understanding of protein aggregation and amyloid formation in vitro and in vivo presents several challenges that remain to be addressed and several fundamental questions about the molecular and structural determinants of amyloid formation and toxicity and the mechanisms of amyloid-induced toxicity remain unanswered. To address this knowledge gap and technical challenges, there is a critical need for developing novel tools and experimental approaches that will not only permit the detection and monitoring of molecular events that underlie this process but also allow for the manipulation of these events in a spatial and temporal fashion both in and out of the cell. This review is primarily dedicated in highlighting recent results that illustrate how advances in chemistry and chemical biology have been and can be used to address some of the questions and technical challenges mentioned above. We believe that combining recent advances in the development of new fluorescent probes, imaging tools that enabled the visualization and tracking of molecular events with advances in organic synthesis, and *Corresponding author. E-mail address: hilal.lashuel@epfl.ch.† M.H. and B.F. contributed equally to this work. Abbreviations used: Aβ, amyloid-β; IAPP, islet amyloid polypeptide; ThT, thioflavin T; TFA, trifluoroacetic acid; TEM, transmission electron microscopy; DMDA, N,N-dimethylethylenediamine; PEG, polyethylene glycol; CNB, α-carboxyl-2-nitrobenzyl; LMW, low molecular weight; AD, Alzheimer's disease; PICUP, photoinduced protein cross-linking of unmodified proteins; tfmd, trifluoromethyldiazirine; SPPS, solid-phase peptide synthesis; PTM, posttranslational modification; LB, Lewy body; NCL, native chemical ligation; EPL, expressed protein ligation; TEV, tobacco etch virus; α-syn, α-synuclein; PD, Parkinson's disease; GPI, glycosylphosphatidylinositol; DOPC, dioleoyl-sn-glycero-3-phosphocholine; SUV, small unilamellar vesicle; CPP, cell-penetrating peptide. novel approaches for protein synthesis and engineering provide unique opportunities to gain a molecular-level understanding of the process of amyloid formation. We hope that this review will stimulate further research in this area and catalyze increased collaboration at the interface of chemistry...

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