Referencia

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

Autores

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.

Resumen

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.

Descripción

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.

Ir al artículo

¿Acabas de publicar un artículo interesante?

Manda la referencia a través de nuestro formulario.  Límite de edad 32 años. Los artículos seleccionados serán destacados como artículos del mes y participarán en el Premio al mejor artículo de jóvenes de la SEBBM, que se entregará en el congreso de la SEBBM (inscripción y alojamiento gratuitos).

Otros "Artículos del mes"

Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis

25-04-2021

Chronic kidney disease (CKD) remains a major epidemiological, clinical, and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) present a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO)...

Leer más

Astrocyte-mediated switch in spike timing-dependent plasticity during hippocampal development

29-03-2021

Presynaptic spike timing-dependent long-term depression (t-LTD) at hippocampal CA3-CA1 synapses is evident until the 3rd postnatal week in mice, disappearing during the 4th week. At more mature stages, we found...

Leer más

Ceramide chain length–dependent protein sorting into selective endoplasmic reticulum exit sites

22-02-2021

Protein sorting in the secretory pathway is crucial to maintain cellular compartmentalization and homeostasis. In addition to coat-mediated sorting, the role of lipids in driving protein sorting during secretory transport...

Leer más

Antigen retrieval and clearing for whole-organ immunofluorescence by FLASH

25-01-2021

Advances in light-sheet and confocal microscopy now allow imaging of cleared large biological tissue samples and enable the 3D appreciation of cell and protein localization in their native organ environment...

Leer más

Viral Bcl2s' transmembrane domain interact with host Bcl2 proteins to control cellular apoptosis

08-01-2021

Viral control of programmed cell death relies in part on the expression of viral analogs of the B-cell lymphoma 2 (Bcl2) protein known as viral Bcl2s (vBcl2s). vBcl2s control apoptosis...

Leer más

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFß after myocardial infarction

01-12-2020

Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood...

Leer más

Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics

30-10-2020

Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic...

Leer más

Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas

01-10-2020

C3G is a guanine nucleotide exchange factor (GEF) that regulates cell adhesion and migration by activating the GTPase Rap1. The GEF activity of C3G is stimulated by the adaptor proteins...

Leer más

Expression of the long non-coding RNA TCL6 is associated with clinical outcome in pediatric B-cell acute lymphoblastic leukemia

31-08-2020

The reciprocal translocation t(12;21)(p13;q22)[ETV6/RUNX1] is the most frequent chromosomal rearrangement in pediatric B-cell acute lymphoblastic leukemia(B-ALL). Long non-coding RNAs (lncRNAs) play important roles in numerous diseases and they represent an...

Leer más

Evaluation of different approaches used to study membrane permeabilization by actinoporins on model lipid vesicles

30-07-2020

Release of aqueous contents from model lipid vesicles has been a standard procedure to evaluate pore formation efficiency by actinoporins, such as sticholysin II (StnII), for the last few decades...

Leer más

Socios Protectores