Parkinson's disease (PD) is a neurodenerative debilitating disorder characterized by progressive disturbances in motor, autonomic and psychiatric functions. The pathological hallmark of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta, which causes striatal dopamine deficiency. Although most PD cases are sporadic (iPD), approximately 5-10% of all patients suffer from monogenic PD forms caused by highly penetrant rare mutations segregating with the disease in families (fPD). One of the genes linked to monogenic PD is DJ-1. Mutations in DJ-1 cause autosomal recessive early-onset forms of fPD; however, it has been shown that an over-oxidized and inactive form of the DJ-1 protein is found in the brains of iPD individuals. Valuable insights into potential PD pathogenic mechanisms involving DJ-1 have been obtained from studies in cell and animal PD models based on DJ-1 deficiency such as Drosophila. Flies mutant for the DJ-1β gene, the Drosophila ortholog of human DJ-1, exhibited disease-related phenotypes such as motor defects, increased reactive oxygen species production and high levels of protein carbonylation. In the present study, we show that loss of DJ-1β function significantly increased the activities of several regulatory glycolytic enzymes. Similar results were obtained in DJ-1-deficient SH-SY5Y neuroblastoma cells, thus suggesting that loss of DJ-1 function in both PD models produces an enhancement of glycolysis. Our results also show that FDA-approved compounds such as meclizine and dimethyl fumarate, which have different clinical applications, are able to attenuate PD-related phenotypes in both models.Moreover, we found that they could exert their beneficial effect by increasing glycolysis through the activation of key glycolytic enzymes. Taken together, these results are consistent with the idea that increasing glycolysis could be a potential disease-modifying strategy for PD, as recently suggested. Besides, they also support further evaluation and potential repurposing of meclizine and dimethyl fumarate as modulators of energy metabolism for neuroprotection in PD.

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Parkinson's disease (PD) is the second most common neurodegenerative disorder and is mainly characterized by the selective and progressive loss of dopaminergic neurons, accompanied by locomotor defects. Although most PD cases are sporadic, several genes are associated with rare familial forms of the disease. Analyses of their function have provided important insights into the disease process, demonstrating that three types of cellular defects are mainly involved in the formation and/or progression of PD: abnormal protein aggregation, oxidative damage, and mitochondrial dysfunction. These studies have been mainly performed in PD models created in mice, fruit flies, and worms. Among them, Drosophila has emerged as a very valuable model organism in the study of either toxin-induced or genetically linked PD. Indeed, many of the existing fly PD models exhibit key features of the disease and have been instrumental to discover pathways relevant for PD pathogenesis, which could facilitate the development of therapeutic strategies.

Mutations in the DJ-1 gene cause autosomal recessive, early-onset Parkinsonism. The DJ-1 protein exerts a protective role against oxidative stress damage, working as a cellular oxidative stress sensor, and it seems to regulate gene expression at different levels. In Drosophila, two DJ-1 orthologs have been identified: DJ-1alpha and DJ-1beta. Several studies have shown that loss of DJ-1beta function causes Parkinson's disease (PD)-like phenotypes in flies such as age-dependent locomotor defects, reduced lifespan, and enhanced sensitivity to toxins that induce oxidative stress, like the herbicide paraquat. However, no dopaminergic neurodegeneration is observed. These results suggested that both locomotor and lifespan phenotypes could be either related to defects in oxidative stress response, or in dopaminergic physiology as proposed in mice models. In this study, we have employed pharmacological approaches to modify the lifespan phenotype of DJ-1beta mutant flies. We have assessed the effects of chronic treatments with antiparkinsonian drugs as well as with antioxidant compounds on such phenotype finding that only antioxidants show statistically significant beneficial effects on DJ-1beta mutants' lifespan. These results strongly suggest that oxidative stress plays a causal role in the lifespan phenotype of DJ-1beta mutants. Consistent with this, we find that loss of DJ-1beta function results in cellular accumulation of reactive oxygen species (ROS) in adult brains, elevated levels of lipid peroxidation and an increased catalase enzymatic activity, thus indicating the existence of high oxidative stress levels in DJ-1beta mutants and confirming the essential function of the DJ-1beta protein in protecting the organism against oxidative insults. Our study further shows that the lifespan phenotype of DJ-1beta mutant flies is amenable to pharmacological intervention, and validates Drosophila as a valuable model for testing and identifying new drugs with therapeutic potential for PD.

Collective and directed cell movements are crucial for diverse developmental processes in the animal kingdom, but they are also involved in wound repair and disease. During these processes groups of cells are oriented within the tissue plane, which is referred to as planar cell polarity (PCP). This requires a tight regulation that is in part conducted by the PCP pathway. Although this pathway was initially characterized in flies, subsequent studies in vertebrates revealed a set of conserved core factors but also effector molecules and signal modulators, which build the fundamental PCP machinery. The PCP pathway in Drosophila regulates several developmental processes involving collective cell movements such as border cell migration during oogenesis, ommatidial rotation during eye development, and embryonic dorsal closure. During vertebrate embryogenesis, PCP signaling also controls collective and directed cell movements including convergent extension during gastrulation, neural tube closure, neural crest cell migration, or heart morphogenesis. Similarly, PCP signaling is linked to processes such as wound repair, and cancer invasion and metastasis in adults. As a consequence, disruption of PCP signaling leads to pathological conditions. In this review, we will summarize recent findings about the role of PCP signaling in collective cell movements in flies and vertebrates. In addition, we will focus on how studies in Drosophila have been relevant to our understanding of the PCP molecular machinery and will describe several developmental defects and human disorders in which PCP signaling is compromised. Therefore, new discoveries about the contribution of this pathway to collective cell movements could provide new potential diagnostic and therapeutic targets for these disorders.