Document Detail


On the mechanism of nonspecific inhibitors of protein aggregation: dissecting the interactions of alpha-synuclein with Congo red and lacmoid.
MedLine Citation:
PMID:  19645507     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Increasing evidence links the misfolding and aberrant self-assembly of proteins with the molecular events that underlie a range of neurodegenerative diseases, yet the mechanistical details of these processes are still poorly understood. The fact that many of these proteins are intrinsically unstructured makes it particularly challenging to develop strategies for discovering small molecule inhibitors of their aggregation. We present here a broad biophysical approach that enables us to characterize the mechanisms of interaction between alpha-synuclein, a protein whose aggregation is closely connected with Parkinson's disease, and two small molecules, Congo red and Lacmoid, which inhibit its fibrillization. Both compounds are found to interact with the N-terminal and central regions of the monomeric protein although with different binding mechanisms and affinities. The differences can be attributed to the chemical nature of the compounds as well as their abilities to self-associate. We further show that alpha-synuclein binding and aggregation inhibition are mediated by small oligomeric species of the compounds that interact with distinct regions of the monomeric protein. These findings provide potential explanations of the nonspecific antiamyloid effect observed for these compounds as well as important mechanistical information for future drug discovery efforts targeting the misfolding and aggregation of intrinsically unstructured proteins.
Authors:
Christofer Lendel; Carlos W Bertoncini; Nunilo Cremades; Christopher A Waudby; Michele Vendruscolo; Christopher M Dobson; Dale Schenk; John Christodoulou; Gergely Toth
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemistry     Volume:  48     ISSN:  1520-4995     ISO Abbreviation:  Biochemistry     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-01     Completed Date:  2009-09-25     Revised Date:  2012-02-27    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8322-34     Citation Subset:  IM    
Affiliation:
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
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MeSH Terms
Descriptor/Qualifier:
Congo Red / metabolism*
Humans
Microscopy, Atomic Force
Molecular Sequence Data
Molecular Structure
Neurodegenerative Diseases / metabolism*
Parkinson Disease / metabolism
Protein Conformation
Protein Folding
Signal Transduction
Small Molecule Libraries / metabolism
Spectrophotometry, Ultraviolet
alpha-Synuclein / chemistry*,  metabolism
Grant Support
ID/Acronym/Agency:
//Wellcome Trust
Chemical
Reg. No./Substance:
0/Small Molecule Libraries; 0/alpha-Synuclein; 573-58-0/Congo Red

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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