Chemical strategies for controlling protein folding and elucidating the molecular mechanisms of amyloid formation and toxicity

Sara Butterfield, Mirva Hejjaoui, Bruno Fauvet, Loay Awad, Hilal A. Lashuel

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 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 and biology to decipher the mechanisms and roles of protein folding, misfolding, and aggregation in health and disease.

Original languageEnglish
Pages (from-to)204-236
Number of pages33
JournalJournal of Molecular Biology
Volume421
Issue number2-3
DOIs
Publication statusPublished - 10 Aug 2012
Externally publishedYes

Fingerprint

Protein Folding
Amyloid
Amyloidogenic Proteins
Biophysics
Protein Engineering
Synthetic Chemistry Techniques
Fluorescent Dyes
Neurodegenerative Diseases
Biochemistry
Alzheimer Disease
Cell Culture Techniques
Pathology
Health
Research
Proteins

Keywords

  • amyloid
  • chemical biology
  • fibrils
  • neurodegenerative diseases
  • posttranslational modifications

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Chemical strategies for controlling protein folding and elucidating the molecular mechanisms of amyloid formation and toxicity. / Butterfield, Sara; Hejjaoui, Mirva; Fauvet, Bruno; Awad, Loay; Lashuel, Hilal A.

In: Journal of Molecular Biology, Vol. 421, No. 2-3, 10.08.2012, p. 204-236.

Research output: Contribution to journalArticle

Butterfield, Sara ; Hejjaoui, Mirva ; Fauvet, Bruno ; Awad, Loay ; Lashuel, Hilal A. / Chemical strategies for controlling protein folding and elucidating the molecular mechanisms of amyloid formation and toxicity. In: Journal of Molecular Biology. 2012 ; Vol. 421, No. 2-3. pp. 204-236.
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