Biology subjects

Arooji, O. K.

Publications and source records attributed to Arooji, O. K..

3 recordsLinked to original sources

bioRxiv2026

High-Content Screening Identifies Dithiocarbamates As A Class Of Chemicals That Disrupts TDP-43 Proteostasis

Transactive response DNA-binding protein 43 (TDP-43) aggregation and loss of function are hallmark features of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) among other neurodegenerative diseases. Despite epidemiological evidence linking environmental exposures to neurodegeneration, few toxicants have been directly associated with neurodegeneration. Here, we performed a high-content imaging screen, using a library of over a thousand chemical compounds that are considered high risk for human exposure and identified 21 toxicants that drive TDP-43 aggregation. Among the top chemical hits, five belonged to the dithiocarbamate (DTC) class of thiol-reactive compounds including the agricultural pesticides thiram and ziram. Thiram directly promoted TDP-43 cysteine oxidation and intermolecular crosslinking, whereas ziram induced TDP-43 aggregation via zinc imbalance and enhanced oxidative stress, suggesting DTCs disrupt redox homeostasis. In primary neurons and human iPSC-derived neurons, DTCs led to TDP-43 aggregation and prominent splicing defects consistent with loss of TDP-43 function. In exposed zebrafish, DTCs impaired TDP-43 function and triggered widespread transcriptional changes reflected by perturbed stress response and metabolic signatures. By combining TDP-43 loss of function mutations with chemical exposures, we observed accelerated TDP-43 loss of function and chemical-induced aggregation, supporting a multiple hit mechanism driving TDP-43 dysfunction. Together, these findings identify DTCs, particularly those used as agricultural pesticides, as dominant modifiers of TDP-43 proteostasis and identify redox imbalance and zinc homeostasis as a central molecular mechanism linking toxicant exposure to TDP-43 proteinopathy.

neuroscience↗

bioRxiv2025

Peripheral immune patterns enable robust cross-platform prediction of ALS onset and progression

Amyotrophic lateral sclerosis (ALS) progression rates vary dramatically between patients, yet the basis of this heterogeneity remains elusive, with no prognostic biomarkers existing to guide clinical decisions or stratify patients for therapeutic trials. Here, we identify a network of coordinated immune cell types, which exhibit differential disruption across progression groups. Using mass cytometry (CyTOF) to profile 2.2 million immune cells from 35 ALS patients stratified by progression rate and 9 healthy controls, we find that the extent of immune dysfunction cannot be reflected by examining differences in individual cell type frequencies. In contrast, analyses of correlation patterns between cell types revealed distinct immune organization patterns, where coordination complexity varied with disease progression. Across all progression groups, we observed striking immune reorganization in natural killer (NK) cells and a major shift from B cell/basophil coordination hubs in healthy controls to neutrophil/T cell-dominated patterns in ALS. Having established coordinated immune patterns, we developed machine learning models to further improve our ability to stratify between disease and non-disease cohorts, achieving superior performance compared to models using cell frequencies alone. Central and effector memory (CM/EM) CD4+ T cell interactions emerged as top discriminative features for disease status, while plasmacytoid dendritic cell (pDC) relationships, especially their ratio with regulatory T cells (T-regs), distinguished progression rates, supporting T-reg-based therapeutic approaches. These findings reframe ALS as a disease of immune coordination breakdown, pointing towards cell-type specific therapeutics and biomarkers that may extend beyond ALS to other neurodegenerative diseases characterized by immune dysfunction.

immunology↗

bioRxiv2024

TDP-43 pathology links innate and adaptive immunity in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is the most common fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, Transactive Response DNA Binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 pathology elicits disease-modifying immune responses in ALS remains underexplored. In this study, we demonstrate that TDP-43 pathology is internalized by antigen presenting cells, causes vesicle rupture, and leads to innate and adaptive immune cell activation. Using a multiplex imaging platform, we observed interactions between innate and adaptive immune cells near TDP-43 pathological lesions in ALS brain. We used a mass cytometry-based whole-blood stimulation assay to provide evidence that ALS patient peripheral immune cells exhibit responses to TDP-43 aggregates. Taken together, this study provides a novel link between TDP-43 pathology and ALS immune dysfunction, and further highlights the translational and diagnostic implications of monitoring and manipulating the ALS immune response.

cell biology↗