ArticlePLoS biology2012
Common features at the start of the neurodegeneration cascade.
Article in PLoS biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
36 citing papers in PubMed, 72 citations in OpenAlex.
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- Unfolded and intermediate states of PrP play a key role in the mechanism of action of an antiprion chaperone.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Mechanistic Insights into the Role of Molecular Chaperones in Protein Misfolding Diseases: From Molecular Recognition to Amyloid Disassembly.International journal of molecular sciences · 2020Review
- Depicting Conformational Ensembles of α-Synuclein by Single Molecule Force Spectroscopy and Native Mass Spectroscopy.International journal of molecular sciences · 2019Article
- Probing the Basis of α-Synuclein Aggregation by Comparing Simulations to Single-Molecule Experiments.Biophysical journal · 2019Article
- Atomic force microscopy for single molecule characterisation of protein aggregation.Archives of biochemistry and biophysics · 2019Review
- Neurodegenerative Diseases: Regenerative Mechanisms and Novel Therapeutic Approaches.Brain sciences · 2018Review
- A peptide-display protein scaffold to facilitate single molecule force studies of aggregation-prone peptides.Protein science : a publication of the Protein Society · 2018Article
- The cohesin module is a major determinant of cellulosome mechanical stability.The Journal of biological chemistry · 2018Article
- Partially native intermediates mediate misfolding of SOD1 in single-molecule folding trajectories.Nature communications · 2017Article
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Authors and funding
13 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.