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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doaj-ace39d0bb3a74abdb135fcb523029e9a2021-07-02T17:09:28ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852012-01-01105e100133510.1371/journal.pbio.1001335Common features at the start of the neurodegeneration cascade.Rubén HervásJavier OrozAlbert Galera-PratOscar GoñiAlejandro ValbuenaAndrés M VeraAngel Gómez-SiciliaFernando Losada-UrzáizVladimir N UverskyMargarita MenéndezDouglas V LaurentsMarta BruixMariano Carrión-VázquezAmyloidogenic 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22666178/pdf/?tool=EBI |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
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 |
spellingShingle |
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. PLoS Biology |
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) |
series |
PLoS Biology |
issn |
1544-9173 1545-7885 |
publishDate |
2012-01-01 |
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. |
url |
https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22666178/pdf/?tool=EBI |
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