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1.
Nat Commun ; 10(1): 225, 2019 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-30644384

RESUMEN

Transient oligomeric species formed during the aggregation process of the 42-residue form of the amyloid-ß peptide (Aß42) are key pathogenic agents in Alzheimer's disease (AD). To investigate the relationship between Aß42 aggregation and its cytotoxicity and the influence of a potential drug on both phenomena, we have studied the effects of trodusquemine. This aminosterol enhances the rate of aggregation by promoting monomer-dependent secondary nucleation, but significantly reduces the toxicity of the resulting oligomers to neuroblastoma cells by inhibiting their binding to the cellular membranes. When administered to a C. elegans model of AD, we again observe an increase in aggregate formation alongside the suppression of Aß42-induced toxicity. In addition to oligomer displacement, the reduced toxicity could also point towards an increased rate of conversion of oligomers to less toxic fibrils. The ability of a small molecule to reduce the toxicity of oligomeric species represents a potential therapeutic strategy against AD.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Colestanos/uso terapéutico , Fragmentos de Péptidos/metabolismo , Espermina/análogos & derivados , Péptidos beta-Amiloides/efectos de los fármacos , Animales , Caenorhabditis elegans , Línea Celular Tumoral , Colestanos/farmacología , Evaluación Preclínica de Medicamentos , Fragmentos de Péptidos/efectos de los fármacos , Espermina/farmacología , Espermina/uso terapéutico
2.
Nat Chem Biol ; 11(5): 347-354, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25848931

RESUMEN

Huntington's disease (HD) is a currently incurable neurodegenerative condition caused by an abnormally expanded polyglutamine tract in huntingtin (HTT). We identified new modifiers of mutant HTT toxicity by performing a large-scale 'druggable genome' siRNA screen in human cultured cells, followed by hit validation in Drosophila. We focused on glutaminyl cyclase (QPCT), which had one of the strongest effects on mutant HTT-induced toxicity and aggregation in the cell-based siRNA screen and also rescued these phenotypes in Drosophila. We found that QPCT inhibition induced the levels of the molecular chaperone αB-crystallin and reduced the aggregation of diverse proteins. We generated new QPCT inhibitors using in silico methods followed by in vitro screening, which rescued the HD-related phenotypes in cell, Drosophila and zebrafish HD models. Our data reveal a new HD druggable target affecting mutant HTT aggregation and provide proof of principle for a discovery pipeline from druggable genome screen to drug development.


Asunto(s)
Aminoaciltransferasas/efectos de los fármacos , Aminoaciltransferasas/genética , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/genética , ARN Interferente Pequeño , Aminoaciltransferasas/antagonistas & inhibidores , Animales , Células Cultivadas , Biología Computacional , Drosophila , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Proteína Huntingtina , Ratones , Ratones Endogámicos C57BL , Mutación/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Pez Cebra , Cadena B de alfa-Cristalina/metabolismo
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