Abstract
Dopamine replacement represents the standard therapy for Parkinson’s disease (PD), a common, chronic, and incurable neurological disorder; however, this approach only treats the symptoms of this devastating disease. In the search for novel disease-modifying therapies that target other relevant molecular and cellular mechanisms, Drosophila has emerged as a valuable tool to study neurodegenerative diseases due to the presence of a complex central nervous system, the blood–brain barrier, and a similar neurotransmitter profile to humans. Human PD-related genes also display conservation in flies; DJ-1β is the fly ortholog of DJ-1, a gene for which mutations prompt early-onset recessive PD. Interestingly, flies mutant for DJ-1β exhibit PD-related phenotypes, including motor defects, high oxidative stress (OS) levels and metabolic alterations. To identify novel therapies for PD, we performed an in vivo high-throughput screening assay using DJ-1β mutant flies and compounds from the Prestwick® chemical library. Drugs that improved motor performance in DJ-1ß mutant flies were validated in DJ-1-deficient human neural-like cells, revealing that zaprinast displayed the most significant ability to suppress OS-induced cell death. Zaprinast inhibits phosphodiesterases and activates GPR35, an orphan G-protein-coupled receptor not previously associated with PD. We found that zaprinast exerts its beneficial effect in both fly and human PD models through several disease-modifying mechanisms, including reduced OS levels, attenuated apoptosis, increased mitochondrial viability, and enhanced glycolysis. Therefore, our results support zaprinast as a potential therapeutic for PD in future clinical trials.
Highlights
Parkinson’s disease (PD), a progressive neurodegenerative movement disorder [1], is characterized by resting tremor, muscular rigidity, bradykinesia postural instability, and other1 3 Vol.:(0123456789)molecular and cellular mechanisms in the hope of modifying the underlying disease [8, 9]
To identify novel treatments for PD, we performed an in vivo high-throughput screening (HTS) assay using a Drosophila PD model (DJ-1β inactivation) and compounds from the Prestwick® Chemical Library (PCL) library, which are dissolved in 100% dimethyl sulfoxide (DMSO) at a final concentration of 5 mM
We evaluated the effect of the 1120 PCL drugs on the locomotor ability of DJ-1β mutants by culturing L2 larvae in media supplemented with each compound at a concentration of 10 μM during development and 5 days after fly eclosion, and climbing assays were performed at that age
Summary
Parkinson’s disease (PD), a progressive neurodegenerative movement disorder [1], is characterized by resting tremor, muscular rigidity, bradykinesia postural instability, and other. Functional studies of genes involved in familial PD have led to a better understanding of the mechanisms and molecular pathways underlying PD pathophysiology that may govern/influence progressive neurodegeneration [15,16,17] Mutations in one such gene, DJ-1 ( known as PARK7), associate with an early-onset recessive form of Parkinsonism [18]. We discovered that supplementation with antioxidant compounds efficiently suppressed some of these phenotypes, thereby confirming Drosophila as an amenable model organism to identify and validate new drugs with therapeutic potential in PD patients [31,32,33] Supporting this assumption, we subsequently performed a pilot screen to evaluate the effect of antioxidant, anti-inflammatory, and neuroprotective compounds in DJ-1β mutant flies. Our results support ZAP as a potentially interesting therapy for PD that could exert beneficial effects in future clinical trials
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