Dataset Information

Common features at the start of the neurodegeneration cascade.

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 ?-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.

SUBMITTER: Hervas R

PROVIDER: S-EPMC3362641 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Common features at the start of the neurodegeneration cascade.

Hervás Rubén R Oroz Javier J Galera-Prat Albert A Goñi Oscar O Valbuena Alejandro A Vera Andrés M AM Gómez-Sicilia Angel A Losada-Urzáiz Fernando F Uversky Vladimir N VN Menéndez Margarita M Laurents Douglas V DV Bruix Marta M Carrión-Vázquez Mariano M

PLoS biology 20120529 5

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-mol ...[more]

PMID: 22666178

Similar Datasets

Project description:BACKGROUND: Epidermal growth factor receptor (EGFR) is an attractive therapeutic target for a number of human tumors including non-small cell lung cancer (NSCLC). Most patients with NSCLC and somatic mutations have shown a dramatic initial clinical response to reversible EGFR inhibitors. The clinical efficacy of reversible inhibitors is, however, ultimately limited due to the emergence of drug resistance, which is usually conferred by the EGFR T790M mutation. Importantly, irreversible, synthetic small molecule inhibitors are currently evaluated and some of them have been shown to overcome the acquired resistance that is oftentimes observed in these patients. Thus far, irreversible EGFR inhibitors as a drug class have not received regulatory approval due in part to their poor effectiveness at clinically achievable concentrations. Therefore, there is an urgent need to discover and develop novel, potent irreversible inhibitors against the EGFR T790M mutation. MATERIAL AND METHODS: In the following study, we report a novel "hybrid strategy" to identify irreversible EGFR inhibitors with active scaffolds starting with the identification and extraction of a common chemical reactive feature and a pharmacophore feature. The chemical reactive feature was elucidated by investigating 138 currently known irreversible inhibitors at B3LYP/6-31G(d) level using the density function theory method. The pharmacophore feature was extracted from the same inhibitors using pharmacophore modeling. Based on these unique features, two constraints were set while calibrating the protocols of in silico screening. Compounds bearing these specific features were obtained from the National Cancer Institute diversity database to form our subsequent library. Finally, a structure based virtual screening against the library was conducted using standard protocols validated in our lab. RESULTS: Twenty-eight candidate compounds that demonstrated antitumor activity and that had novel scaffolds different from commonly known quinazoline/quinoline analogs were obtained. The interaction modes between three representative candidates and our model system are similar to that between the model system and the reference compound T-001, which has previously been reported to be one of the most potent of the 138 irreversible inhibitors. CONCLUSION: The hybrid strategy starting with the extraction of common features is an effective approach to design potential irreversible inhibitors with novel scaffolds and therefore to obtain lead molecules in the selection process. These candidates possessing unique scaffolds have a strong likelihood to act as further starting points in the preclinical development of potent irreversible T790M EGFR inhibitors.

Project description:Several neurodegenerative diseases involve loss of catecholamine neurons--Parkinson's disease (PD) is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are lost has been mysterious. Accumulating evidence supports the concept of "autotoxicity"--inherent cytotoxicity caused by catecholamine metabolites. Since vesicular sequestration limits the buildup of toxic products of enzymatic and spontaneous oxidation of catecholamines, a vesicular storage defect could play a pathogenic role in the death of catecholaminergic neurons in a variety of neurodegenerative diseases. In putamen, deficient vesicular storage is revealed in vivo by accelerated loss of (18)F-DOPA-derived radioactivity and post-mortem by decreased tissue dopamine (DA):DOPA ratios; in myocardium in vivo by accelerated loss of (18)F-dopamine-derived radioactivity and post-mortem by increased 3,4-dihydroxyphenylglycol:norepinephrine (DHPG:NE) ratios; and in sympathetic noradrenergic nerves overall in vivo by increased plasma F-dihydroxyphenylacetic acid (F-DOPAC):DHPG ratios. We retrospectively analyzed data from 20 conditions with decreased or intact catecholaminergic innervation, involving different etiologies, pathogenetic mechanisms, and lesion locations. All conditions involving parkinsonism had accelerated loss of putamen (18)F-DOPA-derived radioactivity; in those with post-mortem data there were also decreased putamen DA:DOPA ratios. All conditions involving cardiac sympathetic denervation had accelerated loss of myocardial (18)F-dopamine-derived radioactivity; in those with post-mortem data there were increased myocardial DHPG:NE ratios. All conditions involving localized loss of catecholaminergic innervation had evidence of decreased vesicular storage specifically in the denervated regions. Thus, across neurodegenerative diseases, loss of catecholaminergic neurons seems to be associated with decreased vesicular storage in the residual neurons.

Dataset Information

Common features at the start of the neurodegeneration cascade.

Publications

Common features at the start of the neurodegeneration cascade.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets