Document Detail

Fibrillar α-synuclein and huntingtin exon 1 assemblies are toxic to the cells.
MedLine Citation:
PMID:  22735540     Owner:  NLM     Status:  MEDLINE    
The aggregation of alpha-synuclein (α-syn) and huntingtin (htt) into fibrillar assemblies in nerve and glial cells is a molecular hallmark of Parkinson's and Huntington's diseases. Within the aggregation process, prefibrillar and fibrillar oligomeric species form. Prefibrillar assemblies rather than fibrils are nowadays considered cytotoxic. However, recent reports describing spreading of fibrillar assemblies from one cell to another, in cell cultures, animal models, and brains of grafted patients suggest a critical role for fibrillar assemblies in pathogenesis. Here we compare the cytotoxic effect of defined and comparable particle concentrations of on-assembly pathway oligomeric and fibrillar α-syn and Htt fragment corresponding to the first exon of the protein (HttEx1). We show that homogeneous populations of α-syn and HttEx1 fibrils, rather than their precursor on-assembly pathway oligomers, are highly toxic to cultured cells and induce apoptotic cell death. We document the reasons that make fibrils toxic. We show that α-syn and HttEx1 fibrils bind and permeabilize lipid vesicles. We also show that fibrils binding to the plasma membrane in cultured cells alter Ca(2+) homeostasis. Overall, our data indicate that fibrillar α-syn and HttEx1, rather than their precursor oligomers, are highly cytotoxic, the toxicity being associated to their ability to bind and permeabilize the cell membranes.
Laura Pieri; Karine Madiona; Luc Bousset; Ronald Melki
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-06-19
Journal Detail:
Title:  Biophysical journal     Volume:  102     ISSN:  1542-0086     ISO Abbreviation:  Biophys. J.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-06-27     Completed Date:  2012-10-31     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  0370626     Medline TA:  Biophys J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2894-905     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Laboratoire d'Enzymologie et Biochimie Structurales, Centre Nationale de la Recherche Scientifique, Gif-sur-Yvette, France.
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MeSH Terms
Calcium / metabolism
Caspase 3 / metabolism
Cell Death / drug effects
Cell Line, Tumor
Cell Membrane / drug effects,  metabolism
Enzyme Activation / drug effects
Intracellular Space / drug effects,  metabolism
Nerve Tissue Proteins / chemistry*,  genetics*
Peptide Fragments / chemistry*,  metabolism,  toxicity*
Permeability / drug effects
Protein Multimerization
Protein Structure, Secondary
alpha-Synuclein / chemistry*,  metabolism,  toxicity*
Reg. No./Substance:
0/HTT protein, human; 0/Nerve Tissue Proteins; 0/Peptide Fragments; 0/alpha-Synuclein; 7440-70-2/Calcium; EC 3.4.22.-/Caspase 3

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

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