Category: Parkinson's Disease (Other)
Objective: To validate candidate environmental modifiers in the LIPAD exposomics study using additional cell lines, and test a proposed “gene-mitochondria-environment axis” in regulating LRRK2-Parkinson’s disease (PD) penetrance.
Background: Mutations in LRRK2 cause the most frequent dominantly inherited form of PD and represent an example of reduced penetrance, suggesting that environmental factors may influence disease onset. Exposomics analyses of household dust from the LIPAD cohort identified environmental chemicals differing between manifesting and non-manifesting LRRK2 G2019S mutation carriers. Bisphenol S (BPS), a plasticizer commonly used as a “safer” replacement for bisphenol A, was decreased in unaffected carriers compared with manifesting carriers, implicating BPS as a potential environmental modifiers of PD penetrance.
Method: Midbrain dopaminergic neuron–enriched cultures were generated from induced pluripotent stem cells (iPSCs) derived from manifesting and non-manifesting LRRK2 G2019S carriers and isogenic controls. Neurons were generated via a two-step protocol involving the generation of small molecule neural precursor cells (smNPCs) followed by dopaminergic neuron differentiation. smNPCs and neurons were exposed to BPS. High-content imaging assessed mitochondrial features, while untargeted metabolomics and lipidomics experiments investigated metabolic alterations. Additional multi-omics analyses, including bulk RNA sequencing, are currently ongoing.
Results: Preliminary results indicated that BPS exposure negatively affected mitochondria, leading to a reduction in mitochondrial size in LRRK2-PD neurons compared with isogenic controls. Furthermore, BPS modulated intracellular reactive oxygen species (ROS) levels in a non-monotonic dose-response pattern after 6 and 24 hours of treatment. This pattern suggests that ROS responses vary with concentration rather than increasing linearly, consistent with previous work.
Conclusion: These findings support BPS as a potential modifier of LRRK2-PD penetrance. Ongoing multi-omics analyses will further characterize metabolomic and transcriptional responses to BPS exposure. This work highlights mitochondria as potential integrators of genetic susceptibility and environmental exposures in PD and establishes a pipeline to investigate additional potential modifiers identified in the LIPAD study, including per- and polyfluoroalkyl substances (PFAS).
References: 1. Talavera Andújar B, Pereira SL, Busi SB, et al. Exploring environmental modifiers of LRRK2-associated Parkinson’s disease penetrance: An exposomics and metagenomics pilot study on household dust. Environment International. 2024;194:109151. doi:10.1016/j.envint.2024.109151
2. Trinh J, Schymanski EL, Smajic S, Kasten M, Sammler E, Grünewald A. Molecular mechanisms defining penetrance of LRRK2 -associated Parkinson’s disease. Medizinische Genetik. 2022;34(2):103-116. doi:10.1515/medgen-2022-2127
3. Usnich T, Vollstedt EJ, Schell N, et al. LIPAD (LRRK2/Luebeck International Parkinson’s Disease) Study Protocol: Deep Phenotyping of an International Genetic Cohort. Front Neurol. 2021;12:710572. doi:10.3389/fneur.2021.710572
4. Pang Q, Li Y, Meng L, Li G, Luo Z, Fan R. Neurotoxicity of BPA, BPS, and BPB for the hippocampal cell line (HT-22): An implication for the replacement of BPA in plastics. Chemosphere. 2019;226:545-552. doi:10.1016/j.chemosphere.2019.03.177
To cite this abstract in AMA style:
B. Talavera Andújar, J. Ghelfi, I. Goglia, M. Tziortziou, M. Borsche, C. Klein, E. Schymanski, A. Grünewald. Bisphenol S: A Potential Environmental Modifier of LRRK2-Associated Parkinson’s disease [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/bisphenol-s-a-potential-environmental-modifier-of-lrrk2-associated-parkinsons-disease/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/bisphenol-s-a-potential-environmental-modifier-of-lrrk2-associated-parkinsons-disease/