Biology subjects

Larson, C.

Publications and source records attributed to Larson, C..

4 recordsLinked to original sources

bioRxiv2026

Pre-myelinating oligodendrocyte ADGRG1 is required for axon ensheathment and CNS myelin formation

Myelin is essential for axonal health and rapid propagation of action potentials. In the central nervous system (CNS), myelination is initiated with axon ensheathment by pre-myelinating oligodendrocytes (preOLs), followed by iterative membrane wrapping and longitudinal extension along the axon. The molecular mechanisms that govern preOL development remain largely unknown. In this study, we identify the adhesion G protein-coupled receptor ADGRG1 (also called GPR56) as a key, evolutionarily conserved regulator of this process. We show that ADGRG1 is highly expressed in preOLs and that its conditional deletion in mouse preOLs leads to simplified preOL morphology and defective axon ensheathment, resulting in CNS hypomyelination. Live imaging in zebrafish demonstrated conserved function of Adgrg1 in axon ensheathment. Mechanistically, we show that ADGRG1 promotes preOL maturation by RhoA activation. Collectively, these findings reveal an ADGRG1-mediated RhoA signaling pathway that governs axon ensheathment and myelin formation.

neuroscience↗

bioRxiv2025

High-Throughput Screening and Initial SAR Studies Identify a Novel Sub-micromolar Potent Human cGAS Inhibitor

Cyclic GMP-AMP synthase (cGAS) has emerged as a promising therapeutic target of several human diseases, including Alzheimers disease (AD) and other neurodegenerative disorders. As a cytosolic DNA sensor, cGAS generates an innate immune response to promote neuroinflammation by producing an endogenous agonist of the stimulator of interferon genes (STING), 23-cyclic GMP-AMP (cGAMP), which activates the cGAS-STING pathway. We have performed a high-throughput screening of a chemical library containing over 300K small molecules at the Fisher Drug Discovery Resource Center (DDRC), Rockefeller University (RU), to identify multiple hit inhibitors of human (h)-cGAS. We used a modified Kinase Glo(R) Luminescent Kinase assay, which was earlier developed at RU and later used by multiple groups, including ours, to perform primary screening of the library using h-cGAS. The hit candidates bearing novel scaffolds are structurally diverse and exhibited in vitro activity in the low micromolar range. RU-0610270 or compound (cpd) 1, a sulfonamide derivative, is one of the most potent hits (IC50=1.88 {micro}M), selected for hit expansion and structure-activity relationship (SAR) analysis. We synthesized new analogs of cpd 1 and evaluated them in vitro against h-cGAS to identify cpd 6 (IC50=0.66 {micro}M) as the most potent hit analog. We further profiled cpd 6 and found that it modestly inhibited cGAMP levels by 29% at 30 {micro}M in THP1 cells without detectable toxicity, and by 76% at 100 {micro}M, albeit with a moderate decrease ([~]20%) in cell viability. These results highlight a novel chemical series with promising in vitro activity, providing a starting point for the development of selective and potent human cGAS inhibitors for clinical use.

neuroscience↗

bioRxiv2024

A Genome-Wide Arrayed CRISPR Screen Reveals PLSCR1 as an Intrinsic Barrier to SARS-CoV-2 Entry

Interferons (IFNs) play a crucial role in the regulation and evolution of host-virus interactions. Here, we conducted a genome-wide arrayed CRISPR knockout screen in the presence and absence of IFN to identify human genes that influence SARS-CoV-2 infection. We then performed an integrated analysis of genes interacting with SARS-CoV-2, drawing from a selection of 67 large-scale studies, including our own. We identified 28 genes of high relevance in both human genetic studies of COVID-19 patients and functional genetic screens in cell culture, with many related to the IFN pathway. Among these was the IFN-stimulated gene PLSCR1. PLSCR1 did not require IFN induction to restrict SARS-CoV-2 and did not contribute to IFN signaling. Instead, PLSCR1 specifically restricted spike-mediated SARS-CoV-2 entry. The PLSCR1-mediated restriction was alleviated by TMPRSS2 over-expression, suggesting that PLSCR1 primarily restricts the endocytic entry route. In addition, recent SARS-CoV-2 variants have adapted to circumvent the PLSCR1 barrier via currently undetermined mechanisms. Finally, we investigate the functional effects of PLSCR1 variants present in humans and discuss an association between PLSCR1 and severe COVID-19 reported recently.

immunology↗

bioRxiv2019

MAVS regulates the quality of the antibody response to West-Nile Virus

A key difference that distinguishes viral infections from protein immunizations is the recognition of viral nucleic acids by cytosolic pattern recognition receptors (PRRs) such as RNA-sensing Rig-I-like receptors (RLRs). Insights into the specific functions of cytosolic PRRs in the instruction of adaptive immunity are therefore critical for the understanding of protective immunity to infections. West Nile virus (WNV) infection of mice deficent of MAVS, the essential RLR signaling adaptor, results in a defective adaptive immune response. While this finding suggests a role for RLRs in the instruction of adaptive immunity to WNV, it is difficult to interpret due to the high WNV viremia, associated exessive antigen loads, and pathology in the absence of a MAVS-dependent innate immune response. To overcome these limitations, we have infected MAVS-deficient mice with a single-round-of-infection mutant of WNV called RepliVAX (RWN). RWN-infected MAVS-deficient (MAVSKO) mice failed to produce an effective neutralizing antibody response to WNV despite normal titers of antibodies targeting the viral WNV-E protein. This defect occurred indepedently of antigen loads or overt pathology. The specificity of the antibody response in RWN-infected MAVSKO mice remained unchanged and was still dominated by antibodies that bound the neutralizing lateral ridge (LR) epitope in the DIII domain of WNV-E. Instead, MAVSKO mice produced IgM antibodies, the dominant isotype controlling primary WNV infection, with lower affinity for the DIII domain. Our findings suggest that RLR-dependent signals are important for the quality of the humoral immune response to WNV.

immunology↗