Common features at the start of the neurodegeneration cascade.

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 conform...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/ace39d0bb3a74abdb135fcb523029e9a
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spelling	oai:doaj.org-article:ace39d0bb3a74abdb135fcb523029e9a2021-11-18T05:36:38ZCommon features at the start of the neurodegeneration cascade.1544-91731545-788510.1371/journal.pbio.1001335https://doaj.org/article/ace39d0bb3a74abdb135fcb523029e9a2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22666178/pdf/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Amyloidogenic 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.Rubén HervásJavier OrozAlbert Galera-PratOscar GoñiAlejandro ValbuenaAndrés M VeraAngel Gómez-SiciliaFernando Losada-UrzáizVladimir N UverskyMargarita MenéndezDouglas V LaurentsMarta BruixMariano Carrión-VázquezPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 10, Iss 5, p e1001335 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 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 Common features at the start of the neurodegeneration cascade.
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 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.
format	article
author	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
author_facet	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
author_sort	Rubén Hervás
title	Common features at the start of the neurodegeneration cascade.
title_short	Common features at the start of the neurodegeneration cascade.
title_full	Common features at the start of the neurodegeneration cascade.
title_fullStr	Common features at the start of the neurodegeneration cascade.
title_full_unstemmed	Common features at the start of the neurodegeneration cascade.
title_sort	common features at the start of the neurodegeneration cascade.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/ace39d0bb3a74abdb135fcb523029e9a
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Common features at the start of the neurodegeneration cascade.

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