Biology subjects

Wyatt, A.

Publications and source records attributed to Wyatt, A..

4 recordsLinked to original sources

bioRxiv2025

Inhibition of cathepsin B blocks amyloidogenesis in the mouse models of neurological lysosomal diseases mucopolysaccharidosis type IIIC and sialidosis

Neuronal accumulation of amyloid aggregates is a hallmark of brain pathology in neurological lysosomal storage diseases (LSDs) including mucopolysaccharidoses (MPS), however, the molecular mechanism underlaying this pathology has not been understood. We demonstrate that elevated lysosomal cathepsin B (CTSB) levels and CTSB leakage to the cytoplasm triggers amyloidogenesis in two neurological LSDs. CTSB levels were elevated 3-5-fold in the cortices of mouse models of MPS IIIC (Hgsnat-Geo and HgsnatP304L) and sialidosis (Neu1{Delta}Ex3), as well as in cortical samples of MPS I, IIIA, IIIC and IIID patients. CTSB was found in the cytoplasm of pyramidal layer IV-V cortical neurons containing Thioflavin-S-positive, {beta}-amyloid-positive aggregates consistent with pro-senile phenotype. In contrast, CTSB-deficient MPS IIIC (HgsnatP304L/Ctsb-/-) mice as well as HgsnatP304L and Neu1{Delta}Ex3 mice chronically treated with irreversible brain-penetrable CTSB inhibitor, E64, showed a drastic reduction of neuronal Thioflavin-S-positive/APP-positive deposits. Neurons of HgsnatP304L/Ctsb-/- mice and E64-treated HgsnatP304L mice also showed reduced levels of P62/LC3-positive puncta, GM2 ganglioside and misfolded subunit C of mitochondrial ATP synthase (SCMAS) consistent with restored autophagy. E64 treatment also rescued hyperactivity and reduced anxiety in HgsnatP304L mice implying that CTSB may become a novel pharmacological target for MPS III and similar LSDs.

genetics↗

bioRxiv2024

A heterogenous pharmaco-transcriptomic landscape induced by targeting a single oncogenic kinase

Over-activation of the epidermal growth factor receptor (EGFR) is a hallmark of glioblastoma. However, EGFR-targeted therapies have led to minimal clinical response. While delivery of EGFR inhibitors (EGFRis) to the brain constitutes a major challenge, how additional drug-specific features alter efficacy remains poorly understood. We introduce SCHEMATIC, which integrates multiplex single-cell chemical transcriptomics with deep-generative classification to resolve chemotype-specific and shared programs and apply it to to define the molecular response of glioblastoma to EGFRis. We identify programs that differ by the chemical properties of EGFRis, including induction of adaptive transcription and modulation of immunogenic gene expression. We find that induction of an adaptive transcriptional program is associated with persistence of surviving cells after EGFR inhibition, and that concurrent EGFR/PI3K inhibition attenuates this program. We also find that pro-immunogenic expression changes associated with a subset of tyrphostin-family EGFR inhibitors are accompanied by enhanced antigen-specific cytotoxic T-cell killing in vitro. Our study provides a framework that considers each agents unique and often unknown poly-pharmacology to prioritize compounds pre-clinically that induce favorable molecular responses.

genomics↗

bioRxiv2024

Multicore-fiber microendoscopy for functional cellular in-organ imaging

Microendoscopy enables minimally invasive investigations of organs even within small cavities. Conventional microendoscopy is limited by probe size and often restricted to a single excitation wavelength. We developed and characterized a multichannel microendoscope as thin as 360 {micro}m and recorded functional cellular signals in-situ using custom written software for image processing. The endoscope had an effective resolution of 4.64 {micro}m and resolved subcellular structures of neurons. The system enabled analysis of in-situ calcium responses in murine tracheal brush cells and kidney podocytes. Additionally, ratiometric redox responses were recorded in whole, explanted organs and pancreatic islet culture. The flexibility and simplicity of our approach for imaging a variety of tissues and organs paves the way for in-vivo, longitudinal studies with cellular resolution.

bioengineering↗

bioRxiv2024

Neuronal lysosome transfer to oligodendrocyte precursor cells: a novel mechanism of neuron-glia communication and its role in neurodegenerative disease

Oligodendrocyte precursor cells (OPCs) shape brain function through intricate regulatory mechanisms. Here, we observed that OPC processes establish connections with neuronal somata, with smaller lysosomes positioned near these contact sites. Tracking lysosomes demonstrated neuronal lysosomes were attracted to and released at these contact points, eventually becoming incorporated into OPC processes, suggesting a selective, OPC-evoked release of lysosomes from neuronal soma and their ingestion by OPCs, highlighting a unique lysosome-mediated communication between neurons and OPCs. Diminished branching of OPC processes resulted in fewer neuron-OPC contacts, fostering larger lysosome accumulation in neurons, altered neuronal activity and escalated prevalence of senescent neurons during aging. A similar reduction in OPC branching and neuronal lysosome accumulation was evident in an early-stage Alzheimers disease mouse model. Together, these findings underscore the pivotal role of OPC processes in modulating neuronal activity through direct somatic contact and lysosome ingestion, presenting a prospective therapeutic avenue for addressing neurodegenerative diseases.

neuroscience↗