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Plos Biology : Common Features at the Start of the Neurodegeneration Cascade, Volume 10

By Weissman, Jonathan S.

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Book Id: WPLBN0003922262
Format Type: PDF eBook :
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Reproduction Date: 2015

Title: Plos Biology : Common Features at the Start of the Neurodegeneration Cascade, Volume 10  
Author: Weissman, Jonathan S.
Volume: Volume 10
Language: English
Subject: Journals, Science, Biology
Collections: Periodicals: Journal and Magazine Collection (Contemporary), PLoS Biology
Publication Date:
Publisher: Plos


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Weissman, J. S. (n.d.). Plos Biology : Common Features at the Start of the Neurodegeneration Cascade, Volume 10. Retrieved from

Description : 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 b-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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