Biology subjects

Castonguay, C.-E.

Publications and source records attributed to Castonguay, C.-E..

5 recordsLinked to original sources

bioRxiv2026

Neuronal secretome from bipolar patient-derived neurons alters network function and contains candidate biomarkers for diagnosis and lithium response

Delayed diagnosis and treatment are a major burden to patients with bipolar disorder. While lithium is the most effective treatment against mania, depressive episodes, and suicide, only 30% of patients respond to it fully. Currently there are no reliable methods to predict lithium responsiveness. To address these challenges, we aimed to identify potential diagnostic and treatment response biomarkers for BD, in addition furthering understanding of BD pathophysiology. Here, we leveraged human induced pluripotent stem cell (hiPSC) derived neurons from lithium responsive (LR), lithium non-responsive (LNR), and healthy age-matched controls (CTL). We found extracellular vesicle (EV) cargos from hiPSC-derived neurons are indicative of disease state and treatment-response. Unbiased proteomic and miRNA profiling identified 10 proteins and 13 miRNAs that were differentially expressed in BD EVs relative to CTL, as well as distinct molecular signatures separating LR ad LNR groups. These differences converged on pathways related to synaptic function, neurotrophic signalling, and cellular stress responses. Additionally, we found the BD neuronal secretome alters activity in non-BD neuronal networks. Chronic treatment of CTL cultures with BD neuron-conditioned media modified the proportion of active neurons and the frequency and amplitude of calcium transients in individual neurons. We demonstrate that neuronal EVs contain molecular signatures of disease state and treatment response in BD and identify the BD secretome as an active regulator of neuronal network homeostasis. This study provides novel insights into the pathophysiology of BD and candidate biomarkers for personalized BD diagnosis and treatment selection.

neuroscience↗

bioRxiv2024

A single-cell eQTL atlas of the human cerebellum reveals vulnerability of oligodendrocytes in essential tremor

Essential tremor (ET) is a movement disorder characterized by an upper-limb postural and action tremor. It is one of the most common neurological disorders, affecting 1% of the worldwide population. Despite strong evidence for genetic factors driving the aetiology of ET, the underlying pathophysiology remains poorly understood. To understand the effects of genetic risk factors in ET on the cerebellum, the brain region thought to be affected by the disease, we built a population-scale single-cell atlas of the human cerebellar cortex comprised of over 1 million cells from 109 individuals. Using single-cell expression quantitative trait loci and mendelian randomization, we found evidence of ET-associated variants in the BACE2 locus causally linked to its downregulation in cerebellar oligodendrocytes. We highlight a genetically vulnerable population of BACE2-expressing immature oligodendrocytes, suggestive of demyelination. We also find dysfunctional processes affecting interactions between Golgi cells, Purkinje layer interneurons, and oligodendrocytes in ET. Our study suggests a crucial role for cerebellar oligodendrocytes in the pathogenesis of ET.

genomics↗

bioRxiv2023

Molecular signatures of hyperexcitability and lithium responsiveness in bipolar disorder patient neurons provide alternative therapeutic strategies.

Bipolar disorder (BD) is a multifactorial psychiatric illness affecting about 1% of the world population. The first line treatment, lithium (Li), is effective in only a subset of patients and its mechanism of action remains largely elusive. In the present study, we used iPSC-derived neurons from BD patients responsive (LR) or not (LNR) to lithium and combined electrophysiology, calcium imaging, biochemistry, transcriptomics, and phosphoproteomics to report mechanistic insights into neuronal hyperactivity in BD, and Lis mode of action. We show a selective rescue of neuronal hyperactivity by Li in BD LR neurons through changes in Na+ currents. The whole transcriptome sequencing revealed altered gene expression in BD neurons in pathways related to glutamatergic transmission, and Li selectively altered those involved in cell signaling and ion transport/channel activity. We found the therapeutic effect of Li in BD LR patients was associated with Akt signaling and confirmed that an Akt activator mimics Li effect in BD LR neurons. Further, we showed that AMP-activated protein kinase (AMPK) reduces neural network activity and sodium currents in BD LNR patients. These findings suggest the potential for novel treatment strategies in BD, such as Akt activators in BD LR cases, and the use of AMPK activators for BD LNR patients.

neuroscience↗

bioRxiv2021

Convergent transcriptomic targets of propranolol and primidone identify potential biomarkers for essential tremor

Essential tremor (ET) is one of the most common movement disorders, affecting nearly 5% of individuals over 65 years old. Despite its high heritability, few genetic risk loci for ET have been identified. Recent advances in pharmacogenomics have generated a wealth of data that led to the identification of molecular signatures in response to hundreds of chemical compounds. Among the different forms of data, gene expression has proven to be quite successful for the inference of drug response in cell models. We sought to leverage this approach in the context of ET where many patients are responsive two drugs: propranolol and primidone. Propranolol- and primidone-specific transcriptomic drug targets, as well as convergent gene targets across both drugs, could provide insights into the pathogenesis of ET and identify possible targets of interest for future treatments. In this study, cerebellar DAOY and neural progenitor cells were treated for 5 days with clinical concentrations of propranolol and primidone, after which RNA-sequencing was used to identify differentially expressed genes. The expression of genes previously implicated in genetic and transcriptomic studies of ET and other movement disorders, such as TRAPPC11, were significantly upregulated by propranolol. Pathway enrichment analysis identified multiple terms related to calcium signalling, endosomal sorting, axon guidance, and neuronal morphology. Convergent differentially expressed genes across all treatments and cell types were also found to be significantly more mutationally constrained, implying that they might harbour rare deleterious variants implicated in disease. Furthermore, these genes were enriched within cell types having high expression of ET related genes in both cortical and cerebellar tissues. Altogether, our results highlight potential cellular and molecular mechanisms associated with tremor reduction and identify relevant genetic biomarkers for drug-responsiveness in ET.

genomics↗

bioRxiv2018

The endosomal sorting adaptor HD-PTP is required for ephrin-B:EphB signalling in cell collapse and motor axon guidance

The signalling output of many transmembrane receptors that mediate cell-cell communication is restricted by the endosomal sorting complex required for transport (ESCRT), but the impact of this machinery on Eph tyrosine kinase receptor function is unknown. We identified the ESCRT-associated adaptor protein HD-PTP as part of an EphB2 BioID interactome, and confirmed this association using co-immunoprecipitation. Although HD-PTP loss does not change EphB2 expression, it attenuates the ephrin-B2:EphB2 signalling-induced collapse of cultured cells and axonal growth cones, and results in aberrant guidance of chick spinal motor neuron axons in vivo HD-PTP depletion abrogates ligand-induced EphB2 clustering, and EphB2 and Src family kinase activation. HD-PTP deficiency also accelerates ligand-induced EphB2 degradation, contrasting the phenotypes reported for other cell surface receptors. Our results link Eph signalling to the ESCRT machinery and demonstrate a role for HD-PTP in the earliest steps of ephrin-B:EphB signalling, as well as in obstructing premature receptor depletion.

cell biology↗