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Metabolomic Changes in Idiopathic and GBA1 Parkinson’s Disease

ABSTRACT:

Background Variants in the β-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.

Methods Randomised 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 naïve vs. medicated.

Findings Differences 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.

Interpretation Significant 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.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase, Gas Chromatography MS - positive

PROVIDER: MTBLS10743 | MetaboLights | 2025-09-18

REPOSITORIES: MetaboLights

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Project description:Background: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by both motor and non-motor symptoms, including olfactory dysfunction, which often precedes motor symptoms by several years. However, the underlying mechanisms linking olfactory dysfunction in PD to biological changes remain unclear. Recent studies suggest a potential connection between PD's olfactory dysfunction and alterations in the nasal microbiome and metabolome, but comprehensive investigations are still lacking.This study aims to explore the interplay between nasal microbiota, metabolites, and olfactory function in PD, identify potential biomarkers for early diagnosis, and investigate therapeutic targets for olfactory dysfunction in PD. Methods: From October 1, 2023, to September 30, 2024, 66 potential participants were enrolled, including PD patients with varying degrees of olfactory dysfunction and healthy controls. Nasal samples were collected for 16S rRNA sequencing and metabolomic analysis using GC-MS. The study also used MPTP-induced PD mouse models to assess the protective effects of cholic acid on olfactory function and dopaminergic neurons. Results: The study found significant differences in nasal microbiota composition and metabolite profiles between PD patients and controls, with correlations to the severity of olfactory dysfunction. Specifically, the relative abundances of Corynebacterium, Dolosigranulum, Muribacter, and Moraxella were elevated in the PD group, while the abundances of Hydrogenophaga, Staphylococcus, Klebsiella, and Bacillus decreased. Metabolomic analysis revealed that cholic acid, octanal, hexadecanol, and phytol were significantly altered in PD patients compared to controls, with cholic acid showing potential as a diagnostic biomarker (AUC > 0.97). In MPTP-induced PD mouse models, cholic acid treatment significantly reduced latencies in detecting buried food pellets, and increased tyrosine hydroxylase (TH)-positive fluorescence intensity in the olfactory bulb and substantia nigra. However, cholic acid did not significantly ameliorate motor symptoms in PD mice, as assessed by the open field test, and did not prevent the loss of TH+ cells in the striatum. Conclusion: The findings highlight the interplay between the nasal microbiome, metabolome, and olfactory dysfunction in PD, suggesting that modulating metabolic pathways could be a promising therapeutic strategy. Future research should focus on larger sample sizes, longitudinal studies, and further validation of biomarkers and therapeutic targets to enhance the understanding and management of PD.

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Metabolomic Changes in Idiopathic and GBA1 Parkinson’s Disease

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