Document Detail


Modulation of alpha-synuclein aggregation by dopamine analogs.
MedLine Citation:
PMID:  20169066     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The action of dopamine on the aggregation of the unstructured alpha-synuclein (alpha-syn) protein may be linked to the pathogenesis of Parkinson's disease. Dopamine and its oxidation derivatives may inhibit alpha-syn aggregation by non-covalent binding. Exploiting this fact, we applied an integrated computational and experimental approach to find alternative ligands that might modulate the fibrillization of alpha-syn. Ligands structurally and electrostatically similar to dopamine were screened from an established library. Five analogs were selected for in vitro experimentation from the similarity ranked list of analogs. Molecular dynamics simulations showed they were, like dopamine, binding non-covalently to alpha-syn and, although much weaker than dopamine, they shared some of its binding properties. In vitro fibrillization assays were performed on these five dopamine analogs. Consistent with our predictions, analyses by atomic force and transmission electron microscopy revealed that all of the selected ligands affected the aggregation process, albeit to a varying and lesser extent than dopamine, used as the control ligand. The in silico/in vitro approach presented here emerges as a possible strategy for identifying ligands interfering with such a complex process as the fibrillization of an unstructured protein.
Authors:
Diane Latawiec; Fernando Herrera; Alpan Bek; Valeria Losasso; Michela Candotti; Federico Benetti; Elvio Carlino; Agata Kranjc; Marco Lazzarino; Stefano Gustincich; Paolo Carloni; Giuseppe Legname
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-02-16
Journal Detail:
Title:  PloS one     Volume:  5     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2010  
Date Detail:
Created Date:  2010-02-19     Completed Date:  2010-09-30     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e9234     Citation Subset:  IM    
Affiliation:
Department of Neurobiology, Scuola Internazionale Superiore di Studi Avanzati-International School for Advanced Studies, Trieste, Italy.
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MeSH Terms
Descriptor/Qualifier:
Circular Dichroism
Dopamine / analogs & derivatives*,  chemistry*,  metabolism
Humans
Hydrogen Bonding
Hydrophobicity
Indoles / chemistry,  metabolism
Ligands
Microscopy, Atomic Force
Microscopy, Electron, Transmission
Molecular Dynamics Simulation
Molecular Structure
Oxidation-Reduction
Protein Binding
Protein Conformation
Recombinant Proteins / chemistry,  metabolism,  ultrastructure
Static Electricity
Tyramine / chemistry,  metabolism
Water / chemistry
alpha-Synuclein / chemistry*,  genetics,  metabolism
Chemical
Reg. No./Substance:
0/Indoles; 0/Ligands; 0/Recombinant Proteins; 0/alpha-Synuclein; 1953-54-4/5-hydroxyindole; 51-67-2/Tyramine; 7732-18-5/Water
Comments/Corrections

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