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Título : Common features at the start of the neurodegeneration cascade
Autor : 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
Fecha de publicación : 2012
Editor: Public Library of Science
Resumen: 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.
Identificadores: doi: 10.1371/journal.pbio.1001335
issn: 1544-9173
Citación : PLoS Biology 10 (2012)
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