Biology subjects

Bronstein, J. M.

Publications and source records attributed to Bronstein, J. M..

3 recordsLinked to original sources

bioRxiv2025

Identification of Pesticides Associated with an Increased Risk of Parkinson's Disease using a Multi-Screen Approach

Parkinsons Disease (PD) is a progressive neurodegenerative disease characterized by aggregation and transmission of alpha-synuclein (-syn) protein and loss of dopaminergic neurons. The etiology of PD is multifactorial involving both genetic and environmental factors. Pesticide exposure has been associated with PD, but it is still unclear which of the hundreds of chemically and structurally diverse pesticides confer this association. While there are numerous pesticides currently registered for use in the United States, in this study, we focused on 62 pesticides used in the California Central Valley. We used 2 cell-based screens and a recently developed pesticide-wide association study (PWAS) analysis to identify candidates that increase the risk of PD. One cell-based screen tested for pesticides that alter autophagy and the other tested for their effect on -syn transmission. To establish biological plausibility, pesticides that were positive in all 3 screens were tested for dopaminergic neurotoxicity in an in vivo zebrafish (ZF) model. The autophagy screen resulted in a total of 22 hits for alterations to either autophagosomes (16 hits) and lysosomes (14 hits) out of the 62 pesticides tested. The -syn transmission screen resulted in 29 hits, and the PWAS resulted in 34 hits. Six pesticides were positive in all 3 screens and four of these pesticides induced aminergic neuron loss in ZF larvae. The majority of the pesticides identified in our screens have not previously been implicated as risk factors for PD but should be considered in future studies.

pharmacology and toxicology↗

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↗

bioRxiv2025

An In Vivo Model of Alpha-Synuclein Spread from Gut to Brain

BackgroundParkinsons disease is a progressive neurodegenerative disorder characterized by the presence of pathological aggregation of the protein alpha-synuclein and the loss of dopaminergic neurons in the substantia nigra. There is evidence that misfolding and propagation of alpha-synuclein aggregates through networks of interconnected neurons is responsible for the pathological spread and progressive neuron loss. However, in vivo models demonstrating such pathological progression remain elusive. ResultsThis study utilizes a zebrafish model in order to interrogate the mechanisms of alpha-synuclein toxicity and spread. We describe the development of a zebrafish model of endogenous neuronal human alpha-synuclein expression that causes, in young fish, behavioral and neuronal changes as well as microglia activation. In aged fish, alpha-synuclein expression induces a slow but progressive pathological phenotype manifesting in neuron loss within the gut and the CNS. This model is further utilized to seed gut pathology by incorporating a novel method of feeding human alpha-synuclein preformed fibrils in order to initiate protein misfolding at an early age. The combination of endogenous neuronal expression of alpha-synuclein and the exogenous addition of misfolded protein facilitates the development of brain pathology and subsequent neuron loss in the CNS. In addition to the pathological alterations induced with the fibril feeding model, genetic changes were identified by single cell RNA sequencing. These gene changes resulted in pathway alteration that implicate neurodegenerative disease processes. ConclusionThis model of alpha-synuclein pathology is useful for understanding mechanisms underlying disease initiation and can replicate the progressive development of pathological synuclein accumulation. It has the potential to induce neuron to neuron spread and also offers a way to explore what interventions may prevent such pathological progression.

neuroscience↗