Searching for Small Molecules that Can Break Down Protein Aggregates Involved in Neurodegenerative Disease

Considerable effort in the research community is devoted to the search for small molecule drugs that can break down or inhibit formation of the protein aggregates associated with various forms of neurodegenerative disease. One of these is α-synuclein, a prominent feature of Parkinson's disease. Potential treatments based on clearance of α-synuclein are at varying points in the development and regulatory approval pipeline. The materials here provide one of many examples of continued efforts to produce new drug candidates that can enter that pipeline. This is an uncertain process: scanning the compound libraries for new possibilities has unknown (but certainly low) odds of success in any given case. It is expensive and slow besides, and few sources of funding are willing to roll the dice given those points.

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. Recently, we have developed an accurate and robust high-throughput screening methodology to identify α-synuclein aggregation inhibitors. Here, we exploited this 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 familiar 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.

Link: https://doi.org/10.1073/pnas.1804198115

Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.