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Small Molecule Inhibits α-synuclein Aggregation, Disrupts Amyloid Fibrils, and Prevents Degeneration of Dopaminergic Neurons

Small Molecule Inhibits α-synuclein Aggregation, Disrupts Amyloid Fibrils, and Prevents Degeneration of Dopaminergic Neurons

Jordi Pujols, Samuel Peña-Díaz, Diana F Lázaro, Francesca Peccati, Francisca Pinheiro, Danilo González, Anita Carija, Susanna Navarro, María Conde-Giménez, Jesús García, Salvador Guardiola, Ernest Giralt, etc.

Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):10481-10486.

PMID: 30249646

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4248205	α-Synuclein A30P human			Price

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