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Title: Common features at the start of the neurodegeneration cascade
Authors: Hervás, Rubén; Oroz, Javier; Galera-Prat, Albert; Goñi Ramos, Óscar; Valbuena, Alejandro; Vera, Andrés M.; Gómez-Sicilia, Ángel; Losada-Urzáiz, Fernando; Uversky, Vladimir N.; Menéndez, Margarita; Laurents, Douglas 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.
URI: http://hdl.handle.net/10261/60708
DOI: 10.1371/journal.pbio.1001335
Identifiers: doi: 10.1371/journal.pbio.1001335
issn: 1544-9173
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