Reference

Pujols, J et al. 2018 Proc Natl Acad Sci USA. Doi: 10.1073/pnas.1804198115 cover PNAS

Authors

Jordi Pujols, Samuel Peña, Diana F. Lázaro, Francesca Pecati, Francisca Pinheiro, Danilo González, Anita Carija, Susanna Navarro, Maria Conde, Jesús García, Salvador Guardiola, Ernest Giralt, Xavier Salvatella, Javier Sancho, Mariona Sadupe, Tiago F. Outeiro, Esther Dalfó y Salvador Ventura.

Abstract

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of intracellular protein inclusions, known as Lewy bodies and Lewy neurites, which are mainly composed of α-synuclein. Here, we exploited a high-throughput screening methodology to identify a small molecule (SynuClean-D) able to inhibit α-synuclein aggregation. SynuClean-D significantly reduces the in vitro aggregation of wild-type α-synuclein and the familiar A30P and H50Q variants in a substoichiometric molar ratio. This compound prevents fibril propagation in protein-misfolding cyclic amplification assays and decreases the number of α-synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature α-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity. The treatment with SynuClean-D of two PD Caenorhabditis elegans models, expressing α-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by α-synuclein. SynuClean-D-treated worms show decreased α-synuclein aggregation in muscle and a concomitant motility recovery. More importantly, this compound is able to rescue dopaminergic neurons from α-synuclein-induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson's disease.

Description

La enfermedad de Parkinson es un desorden neurodegenerativo crónico e irreversible. Su origen y progresión están directamente relacionados con el mal plegamiento, y consecuente agregación, de una proteína: la alfa-sinucleína. La formación y propagación de estos agregados tóxicos neurona a neurona conlleva una pérdida masiva de neuronas dopaminérgicas, encargadas de regular el moviemento. Gracias al análisis masivo de más de 14.000 compuestos químicos, hemos identificado una pequeña molécula capaz de bloquear y revertir estos procesos agregación y evitar la propagación de los mismos neurona a neurona, evitando la neurodegeneración en un modelo sencillo de la enfermedad. A día de hoy, synuClean-D representa una molécula prometedora para su desarrollo como terapia contra el Parkinson.

 

 

SSJ

 

REFERENCIA DEL GRUPO INVESTIGADOR

La identificación y estudio de SynuClean-D como inhibidor de la agregación de alfa-sinucleína es un proyecto coordinado por el grupo de Plegamiento de Proteínas y Enfermedades Conformacionales de la Universidad Autónoma de Barcelona. El grupo investigador dirigido por el profesor Salvador Ventura convive en la interfaz entre la bioinformática y la biofísica. Gracias a esta aproximación multidisciplinar, que combina predicciones in sílico y validaciones experimentales, estudian aspectos fundamentales de la bioquímica como son el plegamiento/mal plegamiento de las proteínas y agregación proteica, con el fin de comprender el origen de las enfermedades conformacionales humanas y desarrollar nuevas estrategias terapéuticas.

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