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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The preparation, spectroscopic characterization, and magnetic study of three new oxamidate-bridged nickel(II) dinuclear complexes of formulas ([Ni(Me3[12]aneN3)]2(mu-oa))(PF6)2 (1), ([Ni(Me3[12]aneN3)]2(mu-dmoa))(PF6)2 (2), and ([Ni(Me3[12]aneN3)]2(mu-dpoa))(PF6)2 (3) (Me3[12]aneN3 = 2,4,4-trimethyl-1,5,9-triazacyclododec-1-ene, oa = oxamidate, dmoa = N,N'-dimethyloxamidate, and dpoa = N,N'-diphenyloxamidate) are reported. The crystal structures of two of them (1 and 3) have been determined. 1 and 3 crystallize in the monoclinic system, space group P2(1)/c, with Z = 2 and a = 7.901(4) A, b = 13.597(6) A, c = 17.565(10) A, and beta = 96.46(4) degrees for 1 and a = 13.854(3) A, b = 17.469(4) A, c = 12.543(3) A, and beta = 116.22(3) degrees for 3. The structures of 1 and 3 consist of dinuclear ([Ni(Me3[12]aneN3)]2(mu-oa))2+ and ([Ni(Me3[12]aneN3)]2(mu-dpoa))2+ cations and hexafluorophosphate anions. Each nickel in 1-3 is five-coordinate, and the substitution of the hydrogen atom of the amidate nitrogen of 1 by a methyl (2) or a phenyl (3) group causes a significant modification of the stereochemistry of the nickel(II) ions from square pyramidal toward trigonal bipyramidal (tau values of 0.12 and 0.48 for 1 and 3, respectively). The NOESY spectrum of 3 has allowed us to achieve the assignment of the phenyl protons of the N,N'-diphenyloxamidate. The value of magnetic coupling between the two nickel(II) ions across the oxamidate bridge [J = -57.0 (oa, 1), -38.0 (dmoa, 2) and -30.5 cm(-1) (dpoa, 3)] is very sensitive to this stereochemical change, and its variation is explained on the basis of orbital considerations. DFT type calculations have been performed to analyze and substantiate the trend of the magnetic coupling in 1-3.

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.

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.

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