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Open Access item Common features at the start of the neurodegeneration cascade

Authors:Hervás, R.
Oroz, J.
Galera-Prat, A.
Goñi Ramos, Oscar
Valbuena, A.
Vera, A.M.
Gómez-Sicilia, A.
Losada-Urzáiz, F.
Uversky, V.N.
Menéndez, Margarita
Laurents, D.V.
Bruix, M.
Carrión-Vázquez, Mariano Sixto
Issue Date:2012
Publisher:Public Library of Science
Citation:PLoS Biology 10 (2012)
Abstract:Amyloidogenic neurodegenerative diseases are incurable conditions with high social impact that are typically caused by specific, largely disordered proteins. However, the underlying molecular mechanism remains elusive to established techniques. A favored hypothesis postulates that a critical conformational change in the monomer (an ideal therapeutic target) in these >neurotoxic proteins> triggers the pathogenic cascade. We use force spectroscopy and a novel methodology for unequivocal single-molecule identification to demonstrate a rich conformational polymorphism in the monomer of four representative neurotoxic proteins. This polymorphism strongly correlates with amyloidogenesis and neurotoxicity: it is absent in a fibrillization-incompetent mutant, favored by familial-disease mutations and diminished by a surprisingly promiscuous inhibitor of the critical monomeric β-conformational change, neurotoxicity, and neurodegeneration. Hence, we postulate that specific mechanostable conformers are the cause of these diseases, representing important new early-diagnostic and therapeutic targets. The demonstrated ability to inhibit the conformational heterogeneity of these proteins by a single pharmacological agent reveals common features in the monomer and suggests a common pathway to diagnose, prevent, halt, or reverse multiple neurodegenerative diseases. © 2012 Hervás et al.
Identifiers:doi: 10.1371/journal.pbio.1001335
issn: 1544-9173
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