Identification of potential therapeutic compounds for Parkinson's disease usingDrosophilaand human cell models

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Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. It is caused by a loss of dopaminergic neurons in the substantia nigra pars compacta, leading to a decrease in dopamine levels in the striatum and thus producing movement impairment. Major physiological causes of neurodegeneration in PD are oxidative stress (OS) and mitochondrial dysfunction; these pathophysiological changes can be caused by both genetic and environmental factors. Although most PD cases are sporadic, it has been shown that 5–10% of them are familial forms caused by mutations in certain genes. One of these genes is the DJ-1 oncogene, which is involved in an early-onset recessive PD form. Currently, PD is an incurable disease for which existing therapies are not sufficiently effective to counteract or delay the progression of the disease. Therefore, the discovery of alternative drugs for the treatment of PD is essential. In this study we used a Drosophila PD model to identify candidate compounds with therapeutic potential for this disease. These flies carry a loss-of-function mutation in the DJ-1β gene, the Drosophila ortholog of human DJ-1, and show locomotor defects reflected by a reduced climbing ability. A pilot modifier chemical screen was performed, and several candidate compounds were identified based on their ability to improve locomotor activity of PD model flies. We demonstrated that some of them were also able to reduce OS levels in these flies. To validate the compounds identified in the Drosophila screen, a human cell PD model was generated by knocking down DJ-1 function in SH-SY5Y neuroblastoma cells. Our results showed that some of the compounds were also able to increase the viability of the DJ-1-deficient cells subjected to OS, thus supporting the use of Drosophila for PD drug discovery. Interestingly, some of them have been previously proposed as alternative therapies for PD or tested in clinical trials and others are first suggested in this study as potential drugs for the treatment of this disease.

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