Objective: To identify potential therapeutic compounds for Parkinson’s disease (PD) treatment by combining a phenotype-based high-throughput screening assay in PD model flies with a validation system in SH-SY5Y human neuroblastoma cells.

Background: PD is the most common motor disorder in the world. Although most of PD cases are sporadic, there are familial cases in which some genes are involved. One of them is DJ-1, which causes an early-onset PD. Interestingly, the DJ-1 protein has been reported to be highly oxidized, and probably inactivated, in sporadic cases. Therefore, results obtained in PD models based on DJ-1 inactivation might be useful for sporadic PD cases. Drosophila is a powerful tool to study neurodegenerative diseases. We previously showed that PD model flies mutant for the DJ-1ß gene (ortholog of human DJ-1) display motor defects, reduced life-span and high ROS levels. These phenotypes can be used in preclinical assays to test the efficacy of potentially therapeutic compounds.

Method: We have tested the efficacy of 1120 compounds included in the Prestwick chemical library (PCL) to suppress motor defects of PD model flies. DJ-1ß mutant larvae were treated with the compounds to a final concentration of 10 µM. Five days after eclosion, a climbing assay was performed to test the motor performance of model flies. Positive compounds were validated in DJ-1-deficient human neuroblastoma cells for their ability to reduce oxidative stress (OS)-induced lethality. After validation, dosage-dependent efficiency and mechanisms of action of hit compounds were studied in the cell model.

Results: Among the drugs found to improve locomotor abilities in the Drosophila model during the primary screening, the ninety most effective compounds were tested for their efficacy to reduce OS-induced lethality in the human cell PD model. During this validation step, we found that five compounds were beneficial for DJ-1-deficient cells in a dose dependent manner.

Conclusion: In this work, we have identified several compounds with therapeutic potential to treat PD. The PCL is a collection of drugs already approved by FDA, EMA and other agencies. Therefore, repurposing of candidate compounds is possible, since they already passed the preparatory and clinical trials. Besides, some of the compounds identified have been found to be beneficial in other PD models, which support the effectiveness of our study.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/high-throughput-screening-using-a-drosophila-model-of-parkinsons-disease/