Metabolic Alterations in a Drosophila Model of Parkinson's Disease Based on DJ-1 Deficiency.

Cristina Solana-Manrique,Nuria Paricio,Carolina Hernández-Oliver,Isabel Torregrosa,Martina Palomino-Schätzlein,Antonio Pineda-Lucena,Francisco José Sanz

doi:10.3390/cells11030331

Abstract

Parkinson’s disease (PD) is the second-most common neurodegenerative disorder, whose physiopathology is still unclear. Moreover, there is an urgent need to discover new biomarkers and therapeutic targets to facilitate its diagnosis and treatment. Previous studies performed in PD models and samples from PD patients already demonstrated that metabolic alterations are associated with this disease. In this context, the aim of this study is to provide a better understanding of metabolic disturbances underlying PD pathogenesis. To achieve this goal, we used a Drosophila PD model based on inactivation of the DJ-1β gene (ortholog of human DJ-1). Metabolomic analyses were performed in 1-day-old and 15-day-old DJ-1β mutants and control flies using 1H nuclear magnetic resonance spectroscopy, combined with expression and enzymatic activity assays of proteins implicated in altered pathways. Our results showed that the PD model flies exhibited protein metabolism alterations, a shift fromthe tricarboxylic acid cycle to glycolytic pathway to obtain ATP, together with an increase in the expression of some urea cycle enzymes. Thus, these metabolic changes could contribute to PD pathogenesis and might constitute possible therapeutic targets and/or biomarkers for this disease.

Highlights

Over the last 25 years, neurodegenerative diseases (NDs) have become a significant challenge to general health, especially in older population groups, and are expected to grow in the future due to an increase in life expectancy [1]
We recently demonstrated that DJ-1β mutant flies and DJ-1deficient human neuroblastoma cells showed an increase in the glycolytic pathway [7]
In order to identify additional metabolic changes caused by the loss of DJ-1β function that could contribute to Parkinson’s disease (PD) pathophysiology, we undertook metabolomic analyses in DJ-1β mutants and control flies by NMR spectroscopy

Summary

Introduction

Over the last 25 years, neurodegenerative diseases (NDs) have become a significant challenge to general health, especially in older population groups, and are expected to grow in the future due to an increase in life expectancy [1]. Parkinson’s disease (PD) is the most common motor disorder, affecting more than 1% of the population over 60 years. Multiple pathways and mechanisms seem to participate in PD pathogenesis, such as the accumulation of misfolded protein aggregates, mitochondrial dysfunction, increased oxidative stress (OS), energy failure, neuroinflammation, and genetic mutations [6]. An increase in the glycolytic rate was observed in PD models, suggesting that there is a link between glucose metabolism, cellular bioenergetics, redox homeostasis and neuronal death [7,8]

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