Objective: Identification of metabolic alterations that could be contributing to Parkinson’s disease (PD) physiopathology and become new biomarkers or therapeutic targets for the disease.

Background: DJ-1 is a causative gene for early-onset recessive PD form. It encodes a multifunctional protein implicate in antioxidant response, mitochondrial homeostasis and central carbon metabolism. PD is an incurable neurodegenerative disorder whose underlying pathological mechanisms are still unclear. Currently, PD diagnosis is mainly based on the presence of motor symptoms that appear when neurodegeneration is highly advanced. Therefore, it is urgent to identify molecular alterations associated with the disease in order to find new biomarkers and therapeutical approaches. Accordingly, we have previously demonstrated that a Drosophila and neuron-like human cell PD models based on DJ-1 deficiency exhibit an increase in the activity of several glycolytic enzymes. Indeed, compounds targeting this pathway have been shown to constitute a potential therapeutic approach. Thus, we decided to study other metabolic alterations implicated in PD physiopathology that could lead to discover new biomarkers and therapeutic targets for this disease.

Method: We performed metabolomic analyses in 1 and 15-day-old control and DJ-1β mutant flies (the ortholog of the human DJ-1) by high resolution nuclear magnetic resonance (NMR) spectroscopy. After this, we selected those pathways in which altered metabolites were identified. Next, we studied their activity by gene expression analyses and enzymatic assays of the pathway components.

Results: The metabolomic analysis led to the identification of changes in levels of several metabolites between DJ-1β mutant and control flies pointing to an implication of different pathways in PD physiopathology.  Among them, DJ-1β mutant flies exhibit a decrease in the amino acid content and variations in carbohydrate levels that could be related to impaired tricarboxylic acid (TCA) cycle and the urea cycle. A more exhaustive analysis of these pathways revealed that there is a switch from TCA cycle to glycolysis and that genes involved in the urea cycle present enhanced expression in DJ-1β mutant flies.

Conclusion: There is a link between altered metabolism and PD physiopathology involving the TCA and the urea cycle in the Drosophila PD model. Proteins of these routes may constitute biomarkers and potential therapeutic targets for the disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/metabolic-alterations-in-a-drosophila-model-of-parkinsons-disease/