Journal
PLOS BIOLOGY
Volume 10, Issue 5, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.1001335
Keywords
-
Categories
Funding
- Ministerio de Ciencia e Innovacion [MICINN-BIO2007-67116]
- Consejeria de Educacion de la Comunidad de Madrid [S-0505/MAT/0283]
- Consejo Superior de Investigaciones Cientificas [CSIC-200620F00]
- MICINN [CTQ2010-21567-C02-02, CTQ2008-00080/BQU, BFU2009-10052]
- Fundacion Ferrer
- Fundacion Areces
- CSIC
Ask authors/readers for more resources
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 beta-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available