Journal Article

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

Pinheiro, Francisca, Outeiro, Tiago Fleming, Carija, Anita, Conde-Giménez, María, Giralt, Ernest, Lázaro, Diana F., Salvatella, Xavier, Dalfó, Esther, Pujols, Jordi, Guardiola, Salvador, Ventura, Salvador, Sancho, Javier, Peccati, Francesca, Sodupe, Mariona, González, Danilo, Navarro, Susanna, Peña-Díaz, Samuel, García, Jesús

2018

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Agglomeration / alpha-Synuclein - antagonists & inhibitors / alpha-Synuclein - metabolism / Amyloid / Amyloid - drug effects / Amyloid - metabolism / Animals / Axons / Biological Sciences / Caenorhabditis elegans - drug effects / Caenorhabditis elegans - metabolism / Degeneration / Disaggregation / Dopamine receptors / Dopaminergic Neurons - drug effects / Dopaminergic Neurons - metabolism / Dopaminergic Neurons - pathology / Fibrils / High-throughput screening / High-Throughput Screening Assays / Humans / Inclusions / Lewy bodies / Movement disorders / Muscles / Neuroblastoma - drug therapy / Neuroblastoma - metabolism / Neuroblastoma - pathology / Neurodegeneration / Neurodegenerative diseases / Neurons / Neuroscience / Parkinson Disease - drug therapy / Parkinson Disease - metabolism / Parkinson Disease - pathology / Parkinson's disease / Protein Aggregation, Pathological - drug therapy / Protein Aggregation, Pathological - metabolism / Protein Aggregation, Pathological - pathology / Protein folding / Proteins / Small Molecule Libraries - pharmacology / Synuclein / Toxicity / Tumor Cells, Cultured