Metabolomic Profiling in LRRK2-Related Parkinson's Disease

Abstract

BackgroundMutations in LRRK2 gene represent the most common known genetic cause of Parkinson's disease (PD).Methodology/Principal FindingsWe used metabolomic profiling to identify biomarkers that are associated with idiopathic and LRRK2 PD. We compared plasma metabolomic profiles of patients with PD due to the G2019S LRRK2 mutation, to asymptomatic family members of these patients either with or without G2019S LRRK2 mutations, and to patients with idiopathic PD, as well as non-related control subjects. We found that metabolomic profiles of both idiopathic PD and LRRK2 PD subjects were clearly separated from controls. LRRK2 PD patients had metabolomic profiles distinguishable from those with idiopathic PD, and the profiles could predict whether the PD was secondary to LRRK2 mutations or idiopathic. Metabolomic profiles of LRRK2 PD patients were well separated from their family members, but there was a slight overlap between family members with and without LRRK2 mutations. Both LRRK2 and idiopathic PD patients showed significantly reduced uric acid levels. We also found a significant decrease in levels of hypoxanthine and in the ratios of major metabolites of the purine pathway in plasma of PD patients.Conclusions/SignificanceThese findings show that LRRK2 patients with the G2019S mutation have unique metabolomic profiles that distinguish them from patients with idiopathic PD. Furthermore, asymptomatic LRRK2 carriers can be separated from gene negative family members, which raises the possibility that metabolomic profiles could be useful in predicting which LRRK2 carriers will eventually develop PD. The results also suggest that there are aberrations in the purine pathway in PD which may occur upstream from uric acid.

Receptor-interacting protein (RIP) kinase family

“…73 The kinase activity, GTP-binding (GTPase) and WD40 domain of RIP7 are all reported to be implicated in RIP7's neurotoxicity. [74][75][76][77][78] Although much effort has been made in searching for the molecular mechanism underlying RIP7's function, [79][80][81][82][83][84][85] the pathogenesis of RIP7 mutations in Parkinson's disease remains unclear.…”

Metabolic Profiling and Phenotyping of Central Nervous System Diseases: Metabolites Bring Insights into Brain Dysfunctions

“…PD is mostly idiopathic but can also be of genetic origin. Two metabolic profiling studies of PD patients reveal decreased plasmatic levels of the antioxidant uric acid, the final product of purine metabolism (Bogdanov et al 2008;Johansen et al 2009). One study showed that levels of uric acid are negatively associated with PD and disease progression (Bogdanov et al 2008;Johansen et al 2009).…”

“…Two metabolic profiling studies of PD patients reveal decreased plasmatic levels of the antioxidant uric acid, the final product of purine metabolism (Bogdanov et al 2008;Johansen et al 2009). One study showed that levels of uric acid are negatively associated with PD and disease progression (Bogdanov et al 2008;Johansen et al 2009). Also levels of glutathione were increased strongly reinforcing the contribution of oxidative stress to HD (Bogdanov et al 2008;Johansen et al 2009).…”

“…One study showed that levels of uric acid are negatively associated with PD and disease progression (Bogdanov et al 2008;Johansen et al 2009). Also levels of glutathione were increased strongly reinforcing the contribution of oxidative stress to HD (Bogdanov et al 2008;Johansen et al 2009). Based on the plasmatic variations of 9 metabolites mostly involved in purine metabolism, one study could predict whether the PD was secondary to a genetic mutation or of idiopathic origin (Johansen et al 2009).…”

Recent advances in biomarkers for Parkinson’s disease focusing on biochemicals, omics and neuroimaging

“…Furthermore, these findings showed that LRRK2 patients with the G2019S mutation have unique metabolomic profiles that distinguish them from patients with idiopathic PD. More importantly, asymptomatic LRRK2 carriers can be separated from gene negative family members, which raise the possibility that metabolomic profiles could be useful in predicting which LRRK2 carriers will eventually develop PD [57]. By using inductively coupled plasma-atomic emission spectrophotometry (ICP-AES) and inductively coupled plasma mass spectrometry (ICP-MS) to determine the concentration variations of elements between PD and normal samples, an element linkage map was established.…”