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

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 ?-synuclein. Here, we exploited a high-throughput screening methodology to identify a small molecule (SynuClean-D) able to inhibit ?-synuclein aggregation. SynuClean-D significantly reduces the in vitro aggregation of wild-type ?-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 ?-synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature ?-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity. The treatment with SynuClean-D of two PD Caenorhabditis elegans models, expressing ?-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by ?-synuclein. SynuClean-D-treated worms show decreased ?-synuclein aggregation in muscle and a concomitant motility recovery. More importantly, this compound is able to rescue dopaminergic neurons from ?-synuclein-induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson's disease.

SUBMITTER: Pujols J

PROVIDER: S-EPMC6187188 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Pujols Jordi J Peña-Díaz Samuel S Lázaro Diana F DF Peccati Francesca F Pinheiro Francisca F González Danilo D Carija Anita A Navarro Susanna S Conde-Giménez María M García Jesús J Guardiola Salvador S Giralt Ernest E Salvatella Xavier X Sancho Javier J Sodupe Mariona M Outeiro Tiago Fleming TF Dalfó Esther E Ventura Salvador S

Proceedings of the National Academy of Sciences of the United States of America 20180924 41

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 ...[more]

PMID: 30249646

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Project description:The misfolding and aggregation of amyloid-? (A?) peptides into amyloid fibrils is regarded as one of the causative events in the pathogenesis of Alzheimer's disease (AD). Tanshinones extracted from Chinese herb Danshen (Salvia Miltiorrhiza Bunge) were traditionally used as anti-inflammation and cerebrovascular drugs due to their antioxidation and antiacetylcholinesterase effects. A number of studies have suggested that tanshinones could protect neuronal cells. In this work, we examine the inhibitory activity of tanshinone I (TS1) and tanshinone IIA (TS2), the two major components in the Danshen herb, on the aggregation and toxicity of A?1-42 using atomic force microscopy (AFM), thioflavin-T (ThT) fluorescence assay, cell viability assay, and molecular dynamics (MD) simulations. AFM and ThT results show that both TS1 and TS2 exhibit different inhibitory abilities to prevent unseeded amyloid fibril formation and to disaggregate preformed amyloid fibrils, in which TS1 shows better inhibitory potency than TS2. Live/dead assay further confirms that introduction of a very small amount of tanshinones enables protection of cultured SH-SY5Y cells against A?-induced cell toxicity. Comparative MD simulation results reveal a general tanshinone binding mode to prevent A? peptide association, showing that both TS1 and TS2 preferentially bind to a hydrophobic ?-sheet groove formed by the C-terminal residues of I31-M35 and M35-V39 and several aromatic residues. Meanwhile, the differences in binding distribution, residues, sites, population, and affinity between TS1-A? and TS2-A? systems also interpret different inhibitory effects on A? aggregation as observed by in vitro experiments. More importantly, due to nonspecific binding mode of tanshinones, it is expected that tanshinones would have a general inhibitory efficacy of a wide range of amyloid peptides. These findings suggest that tanshinones, particularly TS1 compound, offer promising lead compounds with dual protective role in anti-inflammation and antiaggregation for further development of A? inhibitors to prevent and disaggregate amyloid formation.

Dataset Information

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

Publications

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

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