Common features at the start of the neurodegeneration cascade.

• Main Authors: Rubén Hervás, Javier Oroz, Albert Galera-Prat, Oscar Goñi, Alejandro Valbuena, Andrés M Vera, Angel Gómez-Sicilia, Fernando Losada-Urzáiz, Vladimir N Uversky, Margarita Menéndez, Douglas V Laurents, Marta Bruix, Mariano Carrión-Vázquez
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2012-01-01
• Series: PLoS Biology
• Online Access: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22666178/pdf/?tool=EBI

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.