Background Genome-wide association studies (GWASs) in Parkinson's disease (PD) have increased the scope of biological knowledge about the disease over the past decade. We sought to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into disease etiology. Methods We performed the largest meta-GWAS of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases (having a first degree relative with PD), and 1.4M controls. We carried out a meta-analysis of this GWAS data to nominate novel loci. We then evaluated heritable risk estimates and predictive models using this data. We also utilized large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type and biological pathway enrichments for the identified risk factors. Additionally we examined shared genetic risk between PD and other phenotypes of interest via genetic correlations followed by Mendelian randomization. Findings We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of PD depending on prevalence. Integrating methylation and expression data within a Mendelian randomization framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested PD loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. Mendelian randomization between cognitive performance and PD risk showed a robust association. Interpretation These data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified. Funding See supplemental materials (Text S2). lead to earlier detection and refined diagnostics, which may help improve clinical trials (4). The generation of copious amounts of public summary statistics created by this effort relating to both the GWAS and subsequent analyses of gene expression and methylation patterns may be of use to investigators planning follow-up functional studies in stem cells or other cellular screens, allowing them to prioritize targets more efficiently using our data as additional evidence. We hope our findings may have some downstream clinical impact in the future such as improved patient stratification for clinical trials and genetically informed drug targets.

We evaluated the role of melatonin in endotoxemia caused by lipopolysaccharide (LPS) in unanesthetized rats. The expression of inducible isoform of nitric oxide synthase (iNOS) and the increase in the oxidative stress seem to be responsible for the failure of lungs, liver, and kidneys in endotoxemia. Bacterial LPS (10 mg/kg b. w) was i.v. injected 6 h before rats were killed and melatonin (10-60 mg/kg b.w.) was i.p. injected before and/or after LPS. Endotoxemia was associated with a significant rise in the serum levels of aspartate and alanine aminotransferases, gamma-glutamyl-transferase, alkaline phosphatase, creatinine, urea, and uric acid, and hence liver and renal dysfunction. LPS also increased serum levels of cholesterol and triglycerides and reduced glucose levels. Melatonin administration counteracted these organ and metabolic alterations at doses ranging between 20 and 60 mg/kg b. w. Melatonin significantly decreased lung lipid peroxidation and counteracted the LPS-induced NO levels in lungs and liver. Our results also show an inhibition of iNOS activity in rat lungs by melatonin in a dose-dependent manner. Expression of iNOS mRNA in lungs and liver was significantly decreased by melatonin (60 mg/kg b. w., 58-65%). We conclude that melatonin inhibits NO production mainly by inhibition of iNOS expression. The inhibition of NO levels may account for the protection of the indoleamine against LPS-induced endotoxemia in rats.

In recent years an increasing amount of data has been published involving melatonin in the control of brain function. The pineal gland exerts a depressive influence on CNS excitability. This activity is linked to melatonin, since pharmacological doses of the hormone prevent seizures in several animal models. In addition, melatonin also has analgesic properties in these species. However, the sites and mechanism of melatonin action are not known. A role for the pineal gland and its hormone melatonin as a homeostatic system controlling brain excitability has been proposed, and GABA-containing neurons may be involved in some central action of melatonin. There is evidence supporting a role of melatonin in the regulation of the GABA-benzodiazepine receptor complex, and it appears that melatonin potentiates this inhibitory neurotransmitter system in brain. Melatonin does not bind to GABA or benzodiazepine binding sites themselves, because in vitro binding data showed that melatonin is a weak competitor of benzodiazepine binding in brain membranes at concentrations greater than 10(-5) M. The effect of melatonin on brain activity also involves the participation of corticotropic and opioid peptides, and the existence of an opioid-antiopioid homeostatic system is proposed, with the GABA-benzodiazepine receptor complex as an effector. Moreover, the interaction of melatonin with corticotropic peptides and mitochondrial benzodiazepine receptors may result in a participation of neurosteroids in the control of GABA activity and function. The most recently available data from biochemical and electrophysiological studies support the possibility that the anticonvulsant and depressive effects of melatonin on neuron activity may depend on its antioxidant and antiexcitotoxic roles, acting as a free radical scavenger and regulating brain glutamate receptors. The full characterization of the nuclear melatonin receptor explains the genomic effects of melatonin, opening a new perspective regarding actions and roles of melatonin as a cellular protector.

Alpha-synuclein (alpha-syn) is an intracellular protein with a high tendency to aggregation. It is the major component of Lewy bodies and may play a key role in the pathogenesis of Parkinson's disease (PD). alpha-Syn is also released by neurons and can be detected in biological fluids, such as plasma. The purpose of this study was to determine whether plasma alpha-syn concentrations are elevated in newly diagnosed PD patients before treatment (nontreated PD group, ntPD; n = 53) and to compare them with concentrations in PD patients with at least 1 year of specific treatment (tPD; n = 42) and in healthy controls (n = 60). Plasma alpha-syn concentrations in the ntPD and tPD groups were similar and significantly higher than in healthy controls. In conclusion, alpha-syn was elevated early in the development of PD and specific PD treatment did not change plasma alpha-syn levels.

Degeneration of nigrostriatal dopaminergic neurons is the major pathogenic substrate of Parkinson's disease (PD). Inhibitors of monoamine oxidase B (MAO-B) have been used in the treatment of PD and at least one of them, i.e., deprenyl, also displays antioxidant activity. Dopamine (DA) autoxidation produces reactive oxygen species implicated in the loss of dopaminergic neurons in the nigrostriatal pathway. In this study we compared the effects of melatonin with those of deprenyl and vitamins E and C in preventing the hydroxyl radical (8OH) generation during DA oxidation. The rate of production of 2,3-dihydroxybenzoate (2,3-DHBA) in the presence of salicylate, an *OH scavenger, was used to detect the in vitro generation of *OH during iron-catalyzed oxidation of DA. The results showed a dose-dependent effect of melatonin, deprenyl and vitamin E in counteracting DA autoxidation, whereas vitamin C had no effect. Comparative analyses between the effect of these antioxidants showed that the protective effect of melatonin against DA autoxidation was significantly higher than that of the other compounds tested. Also, when melatonin plus deprenyl were added to the incubation medium, a potentiation of the antioxidant effect was found. These findings suggest that antioxidants may be useful in brain protection against toxicity of reactive oxygen species produced during DA oxidation, and melatonin, alone or in combination with deprenyl, may be an important component of the brain's antioxidant defenses to protect it from dopaminergic neurodegeneration.