Biology subjects

Manoj, V.

Publications and source records attributed to Manoj, V..

3 recordsLinked to original sources

bioRxiv2025

Hyperexcitability in Alzheimers Disease triggers a compensatoryneuroprotective response via TREK1

Alzheimers Disease (AD) is marked by early hippocampal and neocortical accumulation of amyloid-beta 42 oligomers (A{beta}42o), driving neuronal hyperactivity and synaptic dysfunction years before symptom onset. While two-pore domain leak potassium channels like TREK1 are crucial for maintaining the resting membrane potential of neurons and shaping their excitability profile, their role in major neurodegenerative disorders like AD remains unknown. Here, we discover an activity-dependent upregulation of TREK1 in AD transgenic mice (3xTg and APP/PS1) and cultured hippocampal/cortical neurons, triggered by A{beta}42o -induced hyperactivity. Mechanistically, we show that increased intracellular calcium activates adenylate cyclase 1/8 (AC1/8), initiating a cAMP-PKA signaling cascade that enhances the expression of chromatin regulator CTCF. This increased CTCF in turn enhances the expression of TREK1 both in vitro and in AD transgenic mice. Through a combination of calcium imaging, patch-clamp electrophysiology, immunostaining, and cognitive assays in a hippocampal TREK1 knockdown AD model, we establish that the pathology-associated upregulation of TREK1 constitutes a critical homeostatic brake on neuronal hyperexcitability. This neuronal response is essential for limiting A{beta}42o-mediated synaptic pathology and delaying cognitive decline. Our study identifies a multi-step signaling cascade triggered by A{beta}42o leading to upregulation of TREK1 that functions as an essential compensatory mechanism for neuronal survival in early AD. This study deciphers a cellular mechanism responsible for the preclinical phase of AD characterized by silent buildup of pathology.

neuroscience↗

bioRxiv2025

A First-in-Class Therapy Targeting Transcription-Replication Conflicts Drives Synthetic Lethality in Homologous Recombination Deficient Cancers

Hidden beneath the layer of tumor malignancy lies unchecked proliferation driven by hyperactive transcription, which fosters the formation of RNA:DNA hybrids. These structural intermediates precipitate collisions between the transcription and replication machineries. Central to mitigating this genomic threat is interleukin enhancer-binding factor 2 (ILF2), which orchestrates the recruitment of RNA:DNA helicases to resolve R-loops and, in doing so, reveals cancer cells dependency on stress-mitigating mechanisms to avert genome catastrophe. Our discovery of Molephantin and its lead derivative, NYH0002 is the outcome of delineating ILF2s function. NYH002 exerts direct binding to the ILF2 complex and disrupts RNA:DNA helicase activity to elicit genome-wide DNA breakages. Tumors with elevated cyclin E and E2F1 expression are sensitive to NYH002, while those deficient in homologous recombination repair exhibit lethality. Collectively, these findings position ILF2 as a key regulator of R-loop homeostasis and reveal a therapeutic vulnerability that NYH002 exploits to suppress tumor malignancy.

cancer biology↗

bioRxiv2022

Genomic, transcriptomic, and metabolomic analysis of Traditional Chinese Medicine plant Oldenlandia corymbosa reveals the biosynthesis and mode of action of anti-cancer metabolites

Natural products from traditional medicinal plants are valuable candidates for clinical cancer therapy. Plants from the Oldenlandia-Hedyotis complex are popular ingredients of Traditional Chinese Medicine (TCM), however a major hurdle in the plant bioprospecting process of TCM plants is that the active metabolites, their biosynthetic pathways, and mode of action are often unknown. We show that Oldenlandia corymbosa extracts are active against breast cancer cell lines. To study the genes involved in the biosynthesis of active compounds in this medicinal plant, we assembled a high-quality genome. We show that the main active compound is ursolic acid and that abiotic stresses cause changes in anti-cancer activity, metabolite composition, and gene expression of plants. To reveal the mode of action of ursolic acid, we show that cancer cells undergo mitotic catastrophe, and we identify three high-confidence protein binding targets by Cellular Thermal Shift Assay (CETSA) and reverse docking.

plant biology↗