Rapino F, Natoli T, Limone F, O'Connor E, Blank J, Tegtmeyer M, Chen W, Norabuena E, Narula J, Hazelbaker D, Angelini G, Barrett L, O'Neil A, Beattie UK, Thanos JM, de Rivera H, Sheridan SD, Perlis RH, McCarroll SA, Stevens B, Subramanian A, Nehme R, Rubin LL. 2023. Small-molecule screen reveals pathways that regulate C4 secretion in stem cell-derived astrocytes. Stem cell reports. 18(1):237-253. Pubmed: 36563689 DOI:S2213-6711(22)00551-3


In the brain, the complement system plays a crucial role in the immune response and in synaptic elimination during normal development and disease. Here, we sought to identify pathways that modulate the production of complement component 4 (C4), recently associated with an increased risk of schizophrenia. To design a disease-relevant assay, we first developed a rapid and robust 3D protocol capable of producing large numbers of astrocytes from pluripotent cells. Transcriptional profiling of these astrocytes confirmed the homogeneity of this population of dorsal fetal-like astrocytes. Using a novel ELISA-based small-molecule screen, we identified epigenetic regulators, as well as inhibitors of intracellular signaling pathways, able to modulate C4 secretion from astrocytes. We then built a connectivity map to predict and validate additional key regulatory pathways, including one involving c-Jun-kinase. This work provides a foundation for developing therapies for CNS diseases involving the complement cascade.
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

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Lee Rubin investigates the key molecular mediators of different neurodegenerative diseases, with the ultimate goal of finding effective preclinical therapeutic candidates.

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