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Metabolomics-based identification of metabolic alterations in PARK2.

ABSTRACT: Objective:Parkin is the causative gene for autosomal recessive familial Parkinson's disease (PD), although it remains unclear how parkin dysfunction is involved with the general condition. Recently, serum and/or plasma metabolomics revealed alterations in metabolic pathways that might reflect pathomechanisms of idiopathic PD (iPD). Thus, we hypothesized that serum metabolomics of patients with homozygous or compound heterozygous parkin mutations (namely, PARK2) might reflect metabolic alterations due to parkin dysfunction. Methods:We enrolled 15 PARK2 patients (52 ± 17.6 years) confirmed with homozygous (seven cases) and compound heterozygous (eight cases) parkin mutations, along with 19 healthy age-matched controls (51 ± 11.5 years). We analyzed 830 metabolites from participants' serum using well-established metabolomics technologies, including ultra-high performance liquid chromatography/tandem mass spectroscopy. Results:Based on metabolic profiles, hierarchical matrix analysis can divide samples between control and PARK2 subjects. Profiles from PARK2 patients showed significantly higher levels of fatty acid (FA) metabolites and oxidized lipids, and significantly lower levels of antioxidant, caffeine, and benzoate-related metabolites. Interpretation:Metabolomics can identify specific metabolic alterations in PARK2 patients compared with controls. Alterations in FA metabolites suggest a relationship between parkin function and lipid metabolism. The elevation of oxidized lipids in combination with decreasing antioxidants may reflect general hyperoxidative stress. Decreasing benzoate-related metabolites might be due to the alteration in gut microbiota. Consequently, caffeine and its metabolites may be decreased due to malabsorption. These findings are similar to metabolic alterations in iPD. Thus, serum/plasma metabolomics may reflect the association between parkin dysfunction and parkinsonism.

SUBMITTER: Okuzumi A

PROVIDER: S-EPMC6414487 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Metabolomics-based identification of metabolic alterations in PARK2.

Okuzumi Ayami A Hatano Taku T Ueno Shin-Ichi SI Ogawa Takashi T Saiki Shinji S Mori Akio A Koinuma Takahiro T Oji Yutaka Y Ishikawa Kei-Ichi KI Fujimaki Motoki M Sato Shigeto S Ramamoorthy Sivapriya S Mohney Robert P RP Hattori Nobutaka N

Annals of clinical and translational neurology 20190221 3

<h4>Objective</h4><i>Parkin</i> is the causative gene for autosomal recessive familial Parkinson's disease (PD), although it remains unclear how parkin dysfunction is involved with the general condition. Recently, serum and/or plasma metabolomics revealed alterations in metabolic pathways that might reflect pathomechanisms of idiopathic PD (iPD). Thus, we hypothesized that serum metabolomics of patients with homozygous or compound heterozygous <i>parkin</i> mutations (namely, PARK2) might reflec ...[more]

PMID: 30911576

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Project description:Background: Cigarette smoking is an important environmental risk factor for cardiovascular events of hypertension (HTN). Existing studies have provided evidence supporting altered gut microbiota by cigarette smoking, especially in hypertensive patients. Metabolic biomarkers play a central role in the functional potentials of the gut microbiome but are poorly characterized in hypertensive smokers. To explore whether serum metabolomics signatures and compositions of HTN patients were varied in smokers, and investigate their connecting relationship to gut microbiota, the serum metabolites were examined in untreated hypertensive patients using untargeted liquid chromatography-mass spectrometry (LC/MS) analysis. Results: A dramatic difference and clear separation in community features of circulating metabolomics members were seen in smoking HTN patients compared with the non-smoking controls, according to partial least squares discrimination analysis (PLS-DA) and orthogonal partial least squares discrimination analysis (OPLS-DA). Serum metabolic profiles and compositions of smoking patients with HTN were significantly distinct from the controls, and were characterized by enrichment of 12-HETE, 7-Ketodeoxycholic acid, Serotonin, N-Stearoyl tyrosine and Deoxycholic acid glycine conjugate, and the depletion of Tetradecanedioic acid, Hippuric acid, Glyceric acid, 20-Hydroxyeicosatetraenoic acid, Phenylpyruvic acid and Capric acid. Additionally, the metabolome displayed prominent functional signatures, with a majority proportion of the metabolites identified to be discriminating between groups distributed in Starch and sucrose metabolism, Caffeine metabolism, Pyruvate metabolism, Glycine, serine and threonine metabolism, and Phenylalanine metabolic pathways. Furthermore, the observation of alterations in metabolites associated with intestinal microbial taxonomy indicated that these metabolic members might mediate the effects of gut microbiome on the smoking host. Indeed, the metabolites specific to smoking HTNs were strongly organized into co-abundance networks, interacting with an array of clinical parameters, including uric acid (UA), low-denstiy lipoprotein cholesterol (LDLC) and smoking index. Conclusions: In conclusion, we demonstrated disparate circulating blood metabolome composition and functional potentials in hypertensive smokers, showing a linkage between specific metabolites in blood and the gut microbiome.

Dataset Information

Metabolomics-based identification of metabolic alterations in PARK2.

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Metabolomics-based identification of metabolic alterations in PARK2.

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