Metabolomic Profiling in LRRK2-Related Parkinson's Disease

Krisztina K Johansen,Linda R White,Jan O Aasly,Claire Henchcliffe,Lei Wang,Mikhail Bogdanov,Wayne R Matson,M Flint Beal,Mark R Cookson

doi:10.1371/journal.pone.0007551

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.

Highlights

Parkinson’s disease (PD) was long considered to be largely idiopathic, but several genetic factors have been reported during the last decade
In the initial analysis we analyzed the data from control subjects and idiopathic and LRRK2 PD patients to determine if there were any differences in the metabolomic profiles between these groups
Since healthy family members of LRRK2 PD patients without the mutation could be considered as controls, the data from them were included in this analysis, either separately, or together with control subjects

Summary

Introduction

Parkinson’s disease (PD) was long considered to be largely idiopathic, but several genetic factors have been reported during the last decade. LRRK2, Parkin and PINK1 genes have the most clinical relevance because of their comparatively high frequency [1,2,3,4]. The 6055G .A mutation in the LRRK2 gene, resulting in a G2019S substitution in the LRRK2 protein is common, though the frequency varies dependent on ethnic group [5,6,7]. Disease progression can be followed with functional neuroimaging techniques such as PET and SPECT [9,10], but these techniques have limited availability, are expensive, and are not used in daily clinical practice. Mutations in LRRK2 gene represent the most common known genetic cause of Parkinson’s disease (PD)

Methods

Results

Conclusion