Biology subjects

Paul, K. C.

Publications and source records attributed to Paul, K. C..

3 recordsLinked to original sources

bioRxiv2026

Single-cell RNA sequencing of peripheral blood cells identifies transcriptomic signatures in Parkinson's disease

Parkinsons disease (PD) is a progressive age-related neurodegenerative disorder characterized by both motor and non-motor symptoms. The poorly understood prodromal period, decades-long progression, and disease-phenotype heterogeneity continue to impede the development of preventive and curative therapies. A growing appreciation of immune system changes during the progression of PD suggests that evaluating peripheral immune cells may help identify signatures relevant to disease etiology. We employed single-cell RNA sequencing to profile the transcriptomes of peripheral blood mononuclear cells (PBMCs) from a cohort of 12 patients with PD and 12 healthy controls, equally distributed by sex. Analysis identified gene expression signatures specific to immune cell lineages in PD when compared with healthy controls. Analysis of the dataset indicated that aspects of the PD-related changes were associated with sex, including metabolic and inflammatory changes. Further analysis of myeloid and T cell subsets identified additional pathways and gene expression profiles associated with PD. Trajectory analysis of the myeloid and T cell datasets indicated significant changes in the distribution of cells across states of gene expression in PD compared with controls. This work provides new evidence of peripheral immune cell changes in PD utilizing high-resolution transcriptomics in a cohort powered to analyze sex as a variable. HighlightsTranscriptomic dataset in a cohort powered to analyze immune phenotype in Parkinsons disease Parkinsons disease-specific gene expression signatures in peripheral immune cell lineages Identification of sex differences in the immune cell transcriptome in Parkinsons disease Trajectory analysis identifies changes in immune cell phenotypic distribution in Parkinsons monocytes

immunology↗

bioRxiv2025

The Pesticide Chlorpyrifos Increases the Risk of Parkinson's Disease

Background and PurposePesticides have been associated with an increased risk of Parkinsons disease (PD), but it is unclear which specific pesticides contribute to this association and whether it is causal. Since chlorpyrifos (CPF) exposure has been implicated as a risk factor for PD, we investigated its association to incident PD and if this association is biologically plausible using human, rodent, and zebrafish (ZF) studies. MethodsThe association of CPF with PD was assessed using the UCLA PEG study (829 PD and 824 control subjects), and proximity-based exposure estimates from living or working near agricultural CPF use. For the mammalian studies, 6 months old male C57BL/6 mice were divided into two groups, CPF and controls, for open field, rotarod, and wire hang behavioral testing. Mice were then exposed to CPF in an inhalation chamber (0.65-2.9 mg/m3/day) for 6 hrs./day 5 days/wk., whereas control mice were exposed to vehicle alone. Behavioral tests were performed before and 2.5 months after CPF exposure following a 3-day washout. Mice were then perfused for immunohistochemical analysis. For the mechanistic studies, ZF embryos were treated with CPF (250 nM) 24 hours post fertilization for 5-7 days. Behavioral testing was performed using the Viewpoint Imaging System. Neuronal loss and microglial activation were determined using immunohistochemistry. Neuronal autophagic flux was determined using autophagy modulators in GFP-LC3 transgenic ZF and Western blots. ResultsLong-term residential CPF exposure was linked to an increased risk of developing PD with an odds ratio of 2.68 (CI 1.58-4.55). Mice exposed to aerosolized CPF developed motor impairment and a significant loss of dopaminergic neurons in the substantia nigra and activation of microglia. TH positive neurons in the substantia nigra (SN) had significantly higher levels of phosphoserine 129 (pS129) -synuclein (-syn), a marker for pathological phosphorylated -syn, and ubiquitin. In contrast, neither pS129 -syn or ubiquitin accumulated in TH neurons in the VTA after CPF exposure. Consistent with the mice data, CPF exposure resulted in impairment of locomotor activity and selective loss of aminergic neurons in ZF. We also found an increase in neuronal apoptosis and microglial activation. Importantly, dopamine neuron loss was found to be at least partially dependent on {gamma}1-synuclein (closest functional homologue to human -syn) as neuronal loss did not occur in {gamma}1-synuclein knockout ZF. Using an in vivo ZF assay, we found impaired autophagic flux and an increase in lysosomal labelling within the zebrafish brain. CPF exposure also led to elevated {gamma}1-synuclein and p62 (autophagic cargo protein) levels consistent with impaired degradation. Furthermore, induction of autophagy was protective, supporting the hypothesis that impaired autophagic flux is at least partially responsible for neuron loss following CPF exposure. ConclusionsCPF exposure is associated with an increased risk of developing PD and this association is likely causal since PD-like pathology was recapitulated in animal models. Furthermore, impaired autophagic flux appears to underly this toxicity, a pathway implicated in the pathogenesis of PD.

neuroscience↗

bioRxiv2022

Coupling comprehensive pesticide-wide association study to iPSC dopaminergic screening identifies and classifies Parkinson-relevant pesticides

Parkinsons disease (PD) is a complex, multi-factorial neurodegenerative disease, known to involve genetic, aging-related components, but also to be highly sensitive to environmental factors. In particular, ample evidence links pesticides to PD etiology. Here, establishing a field-to-bench paradigm, we have combined record-based exposure assessment in a population-based epidemiologic study of PD with testing in dopaminergic neurons produced from iPSCs to further identify and classify PD-relevant pesticides. First, agricultural pesticide-application records in California enabled us to investigate exposure to nearly 300 specific pesticides and PD risk in a comprehensive, pesticide-wide association study (PWAS). We implicated long-term exposure to 53 pesticide active ingredients in PD risk and identified their relevant co-exposure profiles. Second, to identify which of these pesticides might contribute to PD through direct effects on dopaminergic neurons, we employed a live-cell imaging screening paradigm in which neurons, definitively identified with a tyrosine hydroxylase reporter, were exposed to 43 of the high-risk pesticides. Using detailed morphometric measures, we found 10 pesticides were directly toxic to these neurons. Further, we analyzed pesticides typically used in combinations in cotton farming. Among these "cotton cluster" pesticides, co-exposures resulted in markedly greater toxicity than any single pesticide. Trifluralin was a pivotal driver of toxicity to dopaminergic neurons and led to marked mitochondrial dysfunction. Our field-to-bench paradigm may prove useful to mechanistically dissect pesticide exposure implicated in PD risk, and guide agricultural policy in the future.

neuroscience↗