A High-Throughput Chemical Screen in DJ-1 beta Mutant Flies Identifies Zaprinast as a Potential Parkinson's Disease Treatment

Autores de CIPF

• Esther Masia Sanchis

  Autor

• 

  Maria Jesus Vicent Docon

  Autor

Participantes ajenos a CIPF

• Sanz, FJ
• Solana-Manrique, C
• Torres, J
• Paricio, N

Grupos de Investigación

• Laboratorio de Polímeros Terapéuticos

  

  Jefe/a de Grupo

  Maria Jesus Vicent Docon

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-1 beta is the fly ortholog of DJ-1, a gene for which mutations prompt early-onset recessive PD. Interestingly, flies mutant for DJ-1 beta 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-1 beta mutant flies and compounds from the Prestwick (R) 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.

Keywords

• Drosophila; Parkinson's disease; Zaprinast; High-throughput screening; Phosphodiesterase inhibitor; GPR35 agonist