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"

Therapeutic targeting of HER2-CB2R heteromers in HER2-positive breast cancer

01-04-2019

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New...

Leer más

p73 regulates ependymal planar cell polarity by modulating actin and microtubule cytoskeleton

01-03-2019

Planar cell polarity (PCP) and intercellular junctional complexes establish tissue structure and coordinated behaviors across epithelial sheets. In multiciliated ependymal cells, rotational and translational PCP coordinate cilia beating and direct...

Leer más

β‐RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9R239X mice

01-02-2019

Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In...

Leer más

Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons

02-01-2019

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...

Leer más

Dynamic acetylation of cytosolic phosphoenolpyruvate carboxykinase toggles enzyme activity between gluconeogenic and anaplerotic reactions

01-12-2018

Cytosolic phosphoenolpyruvate carboxykinase (PCK1) is considered a gluconeogenic enzyme; however, its metabolic functions and regulatory mechanisms beyond gluconeogenesis are poorly understood. Here, we describe that dynamic acetylation of PCK1 interconverts...

Leer más

The Helicase PIF1 Facilitates Resection overSequences Prone to Forming G4 Structures

02-11-2018

DNA breaks are complex lesions that can be repaired either by non-homologous end joining (NHEJ) or by homologous recombination (HR). The decision between these two routes of DNA repair is...

Leer más

Preventing loss of mechanosensation by the nuclear membranes of alveolar cells reduces lung injury in mice during mechanical ventilation

01-10-2018

The nuclear membrane acts as a mechanosensor that drives cellular responses following changes in the extracellular environment. Mechanically ventilated lungs are exposed to an abnormally high mechanical load that may...

Leer más

Oxidative stress is tightly regulated by cytochrome c phosphorylation and respirasome factors in mitochondria

03-09-2018

Respiratory cytochrome c has been found to be phosphorylated at tyrosine 97 in the postischemic brain upon neuroprotective insulin treatment, but how such posttranslational modification affects mitochondrial metabolism is unclear...

Leer más

STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis

01-08-2018

The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of...

Leer más

A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets

02-07-2018

Activation-induced deaminase (AID) initiates antibody diversification in germinal center (GC) B cells through the deamination of cytosines on immunoglobulin genes. AID can also target other regions in the genome, triggering...

Leer más

Socios Protectores