Exploring environmental modifiers of LRRK2-associated Parkinson's disease penetrance: An exposomics and metagenomics pilot study on household dust

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.