Biology subjects

Pavelka, L.

Publications and source records attributed to Pavelka, L..

3 recordsLinked to original sources

bioRxiv2025

Sex-specific microRNA regulators of Parkinson disease: insights from cohort-stratified simulations of compensatory pathway dynamics

Parkinsons disease (PD) exhibits sex differences in prevalence, symptom severity, and progression, suggesting distinct underlying molecular mechanisms. However, the pathophysiological mechanisms remain largely obscure, particularly in the context of the post-transcriptional regulations, where microRNAs (miRNAs) suppress the expression of multiple genes. Bulk transcriptomic data often blur these effects, especially when regulatory patterns vary by sex or cell type. miRNAs have emerged as key regulators of PD-related processes, but their complexity demands computational methods that enable capturing the functional impact at the pathway level. In this study, we investigated how sex may affect miRNA-regulated PD pathways using Boolean modeling across two large PD cohorts, the Parkinsons Progression Markers Initiative (PPMI) and the Luxembourg Parkinsons Study (LuxPark). First, differential expression analysis identified significant variations in miRNA expression between the sexes across both cohorts. These miRNAs were analysed to identify molecular pathways that are over-represented among the predicted targets of the dysregulated microRNAs (i.e. enrichment analysis). The enriched pathways were used to build Boolean models to simulate the effects of sex-specific miRNA dysregulation. These simulations showed consistent male-specific impairment in mitochondrial biogenesis, and respiratory chain activity. Mitophagy and oxidative stress response pathways were also disrupted, alongside dysregulation of autophagy-related protein-folding mechanisms. Our findings suggest that sex-specific miRNA dysregulation contributes to differences in molecular patterns in PD by influencing compensatory related pathways and responses. These results highlight the need for sex-stratified approaches in modeling, translational research, and precision medicine strategies for disease-modifying treatments.

systems biology↗

bioRxiv2020

Gene-corrected Parkinson's disease neurons show the A30P alpha-synuclein point mutation leads to reduced neuronal branching and function

Parkinsons disease is characterised by the degeneration of A9 dopaminergic neurons and the pathological accumulation of alpha-synuclein. In a patient-derived stem cell model, we have generated dopaminergic neurons from an individual harbouring the p.A30P SNCA mutation and compared those neurons against gene-corrected isogenic control cell lines. We have used confocal microscopy to assess the neuronal network, specifically segmenting dopaminergic neurons and have identified image-based phenotypes showing axonal impairment and reduced neurite branching. We show using multi-electrode array (MEA) technology that the neurons carrying the endogenous p.A30P alpha-synuclein mutation are functionally impaired and identified mitochondrial dysfunction as a pathogenic cellular phenotype. We report that against gene-corrected isogenic control cell lines the neurons carrying the p.A30P SNCA mutation have a deficit and are susceptible to the mitochondrial toxin and environmental pesticide Rotenone. Our data supports the use of isogenic cell lines in identifying image-based pathological phenotypes that can serve as an entry point for future disease modifying compound screenings and drug discovery strategies.

neuroscience↗

bioRxiv2019

Parkinson’s disease-associated alterations of the gut microbiome can invoke disease-relevant metabolic changes

Parkinsons disease (PD) is a systemic disease clinically defined by the degeneration of dopaminergic neurons in the brain. While alterations in the gut microbiome composition have been reported in PD, their functional consequences remain unclear. Herein, we first analysed the gut microbiome of patients and healthy controls by 16S rRNA gene sequencing of stool samples from the Luxembourg Parkinsons study (n=147 typical PD cases, n=162 controls). All individuals underwent detailed clinical assessment, including neurological examinations and neuropsychological tests followed by self-reporting questionnaires. Second, we predicted the potential secretion for 129 microbial metabolites through personalised metabolic modelling using the microbiome data and genome-scale metabolic reconstructions of human gut microbes. Our key results include: 1. eight genera and nine species changed significantly in their relative abundances between PD patients and healthy controls. 2. PD-associated microbial patterns statistically depended on sex, age, BMI, and constipation. The relative abundances of Bilophila and Paraprevotella were significantly associated with the Hoehn and Yahr staging after controlling for the disease duration. In contrast, dopaminergic medication had no detectable effect on the PD microbiome composition. 3. Personalised metabolic modelling of the gut microbiomes revealed PD-associated metabolic patterns in secretion potential of nine microbial metabolites in PD, including increased methionine and cysteinylglycine. The microbial pantothenic acid production potential was linked to the presence of specific non-motor symptoms and attributed to individual bacteria, such as Akkermansia muciniphila and Bilophila wardswarthia. Our results suggest that PD-associated alterations of gut microbiome could translate into functional differences affecting host metabolism and disease phenotype.

microbiology↗