[en] Pathogenic variants in the Leucine-rich repeat kinase 2 (LRRK2) gene are a primary monogenic cause of Parkinson's disease (PD). However, the likelihood of developing PD with inherited LRRK2 pathogenic variants differs (a phenomenon known as "reduced penetrance"), with factors including age and geographic region, highlighting a potential role for lifestyle and environmental factors in disease onset. To investigate this, household dust samples from four different groups of individuals were analyzed using metabolomics/exposomics and metagenomics approaches: PD+/LRRK2+ (PD patients with pathogenic LRRK2 variants; n = 11), PD-/LRRK2+ (individuals with pathogenic LRRK2 variants but without PD diagnosis; n = 8), iPD (PD of unknown cause; n = 11), and a matched, healthy control group (n = 11). The dust was complemented with metabolomics and lipidomics of matched serum samples, where available. A total of 1,003 chemicals and 163 metagenomic operational taxonomic units (mOTUs) were identified in the dust samples, of which ninety chemicals and ten mOTUs were statistically significant (ANOVA p-value < 0.05). Reduced levels of 2-benzothiazolesulfonic acid (BThSO3) were found in the PD-/LRRK2+ group compared to the PD+/LRRK2+ . Among the significant chemicals tentatively identified in dust, two are hazardous chemical replacements: Bisphenol S (BPS), and perfluorobutane sulfonic acid (PFBuS). Furthermore, various lipids were found altered in serum including different lysophosphatidylethanolamines (LPEs), and lysophosphatidylcholines (LPCs), some with higher levels in the PD+/LRRK2+ group compared to the control group. A cellular study on isogenic neurons generated from a PD+/LRRK2+ patient demonstrated that BPS negatively impacts mitochondrial function, which is implicated in PD pathogenesis. This pilot study demonstrates how non-target metabolomics/exposomics analysis of indoor dust samples complemented with metagenomics can prioritize relevant chemicals that may be potential modifiers of LRRK2 penetrance.
Disciplines :
Sciences de l’environnement & écologie
Auteur, co-auteur :
TALAVERA ANDÚJAR, Begoña ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Environmental Cheminformatics
CARDOSO PEREIRA, Sandro Lino ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Molecular and Functional Neurobiology > Team Anne GRÜNEWALD
BUSI, Susheel Bhanu ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Systems Ecology > Team Paul WILMES
Usnich, Tatiana; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
Borsche, Max; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany, Department of Neurology, University of Lübeck, Lübeck, Germany
Ertan, Sibel; School of Medicine, Department of Neurology, Koc University, Istanbul, Turkey
Bauer, Peter; CENTOGENE GmbH, Rostock, Germany
Rolfs, Arndt; CENTOGENE GmbH, Rostock, Germany
HEZZAZ, Soraya ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
GHELFI, Jenny ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
Brüggemann, Norbert; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany, Department of Neurology, University of Lübeck, Lübeck, Germany
ANTONY, Paul ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services > Imaging Platform
WILMES, Paul ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Systems Ecology
Klein, Christine; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
GRÜNEWALD, Anne ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
SCHYMANSKI, Emma ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Environmental Cheminformatics
We thank the Metabolomics Platform of the LCSB for their support with the LC-HRMS analysis. Floriane Gavotto is acknowledged for performing the target LC-MS analysis of the bile acids and the help during data processing with TraceFinder. Rashi Halder and all the sequencing platform of the LCSB is acknowledged for performing the sequencing experiment. The Bioimaging Platform of the LCSB is acknowledged for the support with the imaging analysis of the cell-based experiments. Meike Kasten, MD and Eva-Juliane Vollstedt, MD from the Institute of Neurogenetics, University of Luebeck are acknowledged for their contributions to the design and development of the LIPAD study. Prof. Dr. \u00D6zg\u00FCr \u00D6ztop \u00C7akmak and Prof. Dr. Ay\u015Fe Nazl\u0131 Ba\u015Fak from the Department of Neurology, Koc University, Turkey, are acknowledged for their contributions towards the Turkish LRRK2 samples. We thank Dr. Leonid Zaslavsky, Dr. Evan Bolton, and Dr. Tiejun Cheng from the PubChem Team for the help preparing the LRRK2 suspect list of chemicals. Dr. Gianfranco Frigerio is acknowledged for his inputs during the dust sample preparation and data processing. We acknowledge Veronica Codoni for her assistance with the power analysis calculation and its interpretation. The computational analyses presented in this paper were carried out using the HPC facilities at the University of Luxembourg (Homepage | HPC @ Uni.lu, 2024; Varrette et al. 2014). BTA is part of the \u201CMicrobiomes in One Health\u201D PhD training program, which is supported by the PRIDE doctoral research funding scheme (PRIDE/11823097) of the Luxembourg National Research Fund (FNR). ELS acknowledges funding support from the Luxembourg National Research Fund (FNR) for project A18/BM/12341006. AG received funds from the FNR within the framework of the INTER grants \u201CProtectMove I and II\u201D (FNR11250962 and INTER/DFG/19/14429377) and the ATTRACT career development grant \u201CModel-IPD\u201D (FNR9631103). The LIPAD study has been supported by institutional funds (Institute of Neurogenetics, University of L\u00FCbeck), and was partly supported by Centogene GmbH. Moreover, this study was supported by the German Research Foundation (DFG, ProtectMove FOR2488 to CK, NB, and AG).
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