Biology subjects

Young, D. W.

Publications and source records attributed to Young, D. W..

3 recordsLinked to original sources

bioRxiv2026

Druggable CSNK2A1-MeCP2 regulatory axis links Okur-Chung neurodevelopmental syndrome with MECP2-related disorders

The brain is exquisitely sensitive to methyl-CpG-binding protein 2 (MeCP2) abundance. Too little causes Rett syndrome (RTT), too much causes MECP2 duplication syndrome (MDS), and in both, severity tracks with the amount of functional MeCP2. Even modest deviations are detrimental, yet how MeCP2 abundance is controlled remains poorly understood. Using genome-wide CRISPR knockout screens, we identified hundreds of proteins regulating MeCP2, revealing a casein kinase 2 alpha 1 (CSNK2A1)-driven regulatory axis stabilizing MeCP2. We show this axis is druggable and therapeutically relevant, using a novel CSNK2A1 inhibitor in human cells and targeting Csnk2a1 in an MDS mouse model. We further connect CSNK2A1-MeCP2 regulatory disruption to Okur-Chung neurodevelopmental syndrome (OCNDS), caused by mutations in CSNK2A1, finding ~50% less hippocampal MeCP2 in an OCNDS mouse model. Together, these data identify a druggable regulatory axis modulating MeCP2 and implicate MeCP2 dysregulation in the molecular pathogenesis of OCNDS and potentially other neurodevelopmental disorders.

neuroscience↗

bioRxiv2023

SPA-STOCSY: An Automated Tool for Identification of Annotated and Non-Annotated Metabolites in High-Throughput NMR Spectra

Nuclear Magnetic Resonance (NMR) spectroscopy is widely used to analyze metabolites in biological samples, but the analysis can be cumbersome and inaccurate. Here, we present a powerful automated tool, SPA-STOCSY (Spatial Clustering Algorithm - Statistical Total Correlation Spectroscopy), which overcomes the challenges by identifying metabolites in each sample with high accuracy. As a data-driven method, SPA-STOCSY estimates all parameters from the input dataset, first investigating the covariance pattern and then calculating the optimal threshold with which to cluster data points belonging to the same structural unit, i.e. metabolite. The generated clusters are then automatically linked to a compound library to identify candidates. To assess SPA-STOCSYs efficiency and accuracy, we applied it to synthesized and real NMR data obtained from Drosophila melanogaster brains and human embryonic stem cells. In the synthesized spectra, SPA outperforms Statistical Recoupling of Variables, an existing method for clustering spectral peaks, by capturing a higher percentage of the signal regions and the close-to-zero noise regions. In the real spectra, SPA-STOCSY performs comparably to operator-based Chenomx analysis but avoids operator bias and performs the analyses in less than seven minutes of total computation time. Overall, SPA-STOCSY is a fast, accurate, and unbiased tool for untargeted analysis of metabolites in the NMR spectra. As such, it might accelerate the utilization of NMR for scientific discoveries, medical diagnostics, and patient-specific decision making.

bioinformatics↗

bioRxiv2020

Oleic acid triggers hippocampal neurogenesis by binding to TLX/NR2E1

Adult hippocampal neurogenesis underpins learning, memory, and mood, but diminishes with age and illness. The orphan nuclear receptor TLX/NR2E1 is known to regulate neural stem and progenitor cell self-renewal and proliferation, but the precise mechanism by which it accomplishes this is unknown. We found that neural stem and progenitor cells require monounsaturated fatty acids to survive and proliferate. Specifically, oleic acid (18:1{omega}9) binds to TLX to convert it from a transcriptional repressor to a transcriptional activator of cell cycle and neurogenesis genes. We propose a model in which sufficient quantities of this endogenous ligand must bind to TLX to trigger the switch to proliferation. These findings pave the way for future therapeutic manipulations to counteract pathogenic impairments of neurogenesis.

neuroscience↗