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.

Bacterial Metabolites Mirror Altered Gut Microbiota Composition in Patients with Parkinson’s Disease

“…Although it is clear that PD patients have an altered microbiota composition [10][11][12][13][14][15][16][17][18][19][20][21][22], which was reviewed recently [25,26] and updated and merged in Table 1, there is a large variation among studies and there is no clear consensus about which bacteria might be involved, which might be due to several factors including sample storage, technical differences of sampling, sequencing methods, statistical approach, demographics, clinical details, and sample size [10]. Nevertheless, the altered microbiota composition could result in metabolic changes in PD patients which could play an important role in disease onset and progression of PD [24]. Therefore, many studies focused on metabolic biomarker screening (comparing healthy subjects with either familial PD or idiopathic PD), for an early detection of potential development of PD.…”

“…Therefore, many studies focused on metabolic biomarker screening (comparing healthy subjects with either familial PD or idiopathic PD), for an early detection of potential development of PD. The metabolic profiles of PD patients (in cerebrospinal fluid (CSF), blood or urine) usually reflect oxidative stress [24,[27][28][29][30][31] or mitochondrial dysfunction [24,[31][32][33][34][35]. However, many studies also observed differences in metabo-lites from bacterial origin, which are summarized in Table 2.…”

“…Indeed, PD patients have an altered microbiota composition compared to healthy controls (HC) [10][11][12][13][14][15][16][17][18][19][20][21][22], and one of the main bacterial metabolites, short chain fatty acids (SCFA), have been implicated in ␣-synuclein pathology and microglia activation in a mouse model of PD [23]. Altered microbial composition could lead to a shift in circulating bacterial derived metabolites [24], and could be involved in low-grade inflammation, an important trigger for the onset of PD [8]. In this review, we aim to establish a link between the microbial composition and the reported alterations in their metabolic capacity that have profound immune modulating properties, which could potentially trigger onset, progression and etiology of PD.…”

Nonmercaptalbumin as an oxidative stress marker in Parkinson’s and PARK2 disease

“…Functional interactions between parkin/autosomal recessive familial PD due to parkin mutations (PARK2) and PTEN‐induced putative kinase (PINK1)/autosomal recessive familial PD due to PINK1 mutations (PARK6) are essential for mitochondria quality control . Additionally, our previous investigations have shown that oxidative stress markers are relevant in the evaluation of idiopathic PD (iPD) and PARK2, and examining oxidative or redox markers might be useful to understand the pathomechanisms of these diseases …”

“…stress markers are relevant in the evaluation of idiopathic PD (iPD) and PARK2, and examining oxidative or redox markers might be useful to understand the pathomechanisms of these diseases. 10,11 Human nonmercaptalbumin (HNA) is the directly oxidized form of human serum albumin (HSA). 12 The redox ratio of HNA to HSA, defined as %HNA, reflects the systemic oxidative stress.…”