Digital Object Identifier (DOI)
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.
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Citation / Publisher Attribution
PLoS Biology, v. 10, issue 5, art. e1001338
© 2012 Hervás et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Scholar Commons Citation
Hervás, Rubén; Oroz, Javier; Galera-Prat, Albert; Goñi, Oscar; Valbuena, Alejandro; Vera, Andrés M.; Gómez-Sicilia, Àngel; Losada-Urzáiz, Fernando; Uversky, Vladimir N.; Menéndez, Margarita; Laurents, Douglas V.; Bruix, Marta; and Carrión-Vázquez, Mariano, "Common Features at the Start of the Neurodegeneration Cascade" (2012). Molecular Medicine Faculty Publications. 586.