Jiyoen Kim

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.

Astrocytes are key regulators of lipid metabolism, and dysregulated astrocytic lipid processing is implicated in Parkinson’s disease (PD) pathogenesis. Our prior genome-wide screens identified ACSBG1, an astrocyte-enriched acyl-CoA synthetase, as a candidate regulator of α-synuclein (α-Syn) levels. However, how ACSBG1 links lipid reprogramming to inflammatory astrocyte activation and α-Syn pathology remains unknown. We compared the transcriptomic, cytokine, and lipid secretomes of TNF-α and IL-1α stimulated primary astrocytes from wild-type (WT) and Acsbg1 knockout (KO) mice. In vivo, we crossed Acsbg1 KO mice with a Thy1-α-Syn PD model to assess behavior, neuroinflammation, synaptic integrity, and α-Syn levels. Following cytokine exposure, Acsbg1 KO astrocytes mounted an attenuated inflammatory transcriptional response, secreting significantly fewer inflammatory mediators (e.g., IL-6, RANTES, MIP-3α) and less long-chain Sphingosine 20:1 than WT astrocytes. Importantly, exogenous Sphingosine 20:1 or cytokines from WT reactive astrocytes induced neuronal α-Syn phosphorylation (pS129). In vivo, Acsbg1 deletion in Thy1-α-Syn mice reduced astrogliosis, rescued synaptic and behavioral deficits, and decreased total and pS129-α-Syn. These findings establish ACSBG1 as a key regulator of inflammatory astrocyte signaling that contributes to α-Syn phosphorylation via specific cytokine and lipid mediators, identifying ACSBG1 as a novel therapeutic target for modulating astrocyte-neuron communication in PD. Graphical

Kim JH, et al. J Korean Med Sci. 2022 Aug;37(34):e258. https://doi.org/10.3346/jkms.2022.37.e258