Metabolomic Changes in Idiopathic and GBA1 Parkinsons Disease

BackgroundVariants in the {beta}-glucocerebrosidase (GBA1) gene are the commonest genetic risk factor for Parkinson Disease (PD). Here, we use mass spectrometry based metabolomics to analyse serum and sebum samples from 50 genotyped participants and find differences in lipid and sugar regulation, oxidative stress and the production of amino acids and neurotransmitters which distinguish GBA1-PD from iPD. A subset of highly ranked features also correlate to GBA1 variant severity. MethodsRandomised and blinded serum samples from GBA1-PD and iPD participants (n=50) were analysed by Liquid Chromatography - Mass Spectrometry (LC-MS) and Gas Chromatography - Mass Spectrometry (GC-MS), and sebum samples by headspace GC-MS. After deconvolution and alignment of data, three models were created: GBA1-PD vs. iPD, severity of GBA1 variant, and drug naive vs. medicated. FindingsDifferences in metabolomic signatures were seen between GBA1-PD and iPD in sebum and serum with good specificity and sensitivity. Significant pathways in serum included sphingolipid metabolism, amino sugar metabolism and amino acid pathways, whereas significant features between groups in sebum are hypothesised to be lipid degradation products. Several highly ranked features displayed regulation with variant severity. When separating participants according to medication status, we see separation by supervised analysis by all analytical techniques. InterpretationSignificant pathways and metabolites between GBA1-PD and iPD display alterations in sphingolipids. Other features and pathways that may be related include amino sugar metabolism and lipid breakdown products in sebum. Together, significant features indicate possible changes in mechanisms of oxidative stress and neurotransmitter precursors. FundingAHVS thanks the Kattan Trust and Cure Parkinsons for their generous support of this research. PEB thanks the Michael J Fox Foundation (grant ref:12921) BBSRC (grant Ref BB/L015048/1) and Parkinsons UK (grant ref: K-1504) for funding our work. Research In contextO_ST_ABSEvidence before this studyC_ST_ABSVariants in the GBA1 gene are a genetic risk factor for PD, associated with earlier onset and faster progression. GBA1 encodes GCase, and variants can lead to accumulation of glucosylceramide and other substrates. Prior metabolomics studies have found alterations in amino acids (Greuel) and lipids (Guedes) and have noted the complexity of relating glycosphingolipid levels to mutation (den Heijer). Only a handful of studies have investigated variation with mutation severity, and those that exist focus on the presence of proteins such as alpha synuclein or GCase. Further, non-invasively sampled biofluids such as sebum have not been investigated for metabolomic signatures and remain underexplored as sources of biomarkers. Added Value of this studyThis study integrates serum metabolomics with headspace profiling of sebum. Findings reveal differences in lipid and sugar regulation, amino acid pathways and oxidative stress mechanisms. Both serum and sebum reveal differential profiles of GBA1-PD and iPD, as well as containing significant features that display regulation with gene severity. Implications of all the available evidenceThe work demonstrates that GBA1 variants and their severity alter the metabolomic profiles of PD, which can be readout from both serum and sebum. Quantifying the metabolic signatures of differentially dysregulated pathways could be used to target therapeutics for genetically defined PD subtypes and improve understanding of the impacts of gene mutations on disease progression. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/25335343v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1744a9corg.highwire.dtl.DTLVardef@1ce5af9org.highwire.dtl.DTLVardef@b6cddborg.highwire.dtl.DTLVardef@1850507_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG