Abstract
Brain Behav Immun. 2025 Mar 18:S0889-1591(25)00111-4. doi: 10.1016/j.bbi.2025.03.026. Online ahead of print.
ABSTRACT
CUB and sushi multiple domains 1 (CSMD1) is predominantly expressed in brain and robustly associated with schizophrenia risk; however, understanding of which cells express CSMD1 in brain and how it impacts risk is lacking. CSMD1 encodes a large transmembrane protein including fifteen tandem short consensus repeats (SCRs), resembling complement C3 convertase regulators. CSMD1 complement regulatory activity has been reported and mapped to SCR17-21. We expressed two SCR domains of CSMD1, SCR17-21 and SCR23-26, and characterised their complement regulatory activity using a panel of functional assays testing convertase and terminal pathway inhibition. Both domains inhibited the classical pathway C3 convertase by acting as factor I cofactors; neither domain caused any inhibition in alternative or terminal pathway assays. Novel anti-CSMD1 monoclonal antibodies cross-reactive with human and mouse CSMD1 were generated that detected endogenous CSMD1 in human and rodent brain; immunostaining showed predominantly astrocyte and synaptic localisation of CSMD1, the latter confirmed using isolated synapses. Using iPSC-derived cells, astrocyte expression was confirmed and expression on cortical neurons demonstrated. We show that CSMD1 is a classical pathway-specific complement regulator expressed predominantly on astrocytes, neurons, and synapses in human and mouse brain. These findings will help reveal the mechanism by which CSMD1 impacts schizophrenia risk.
PMID:40112933 | DOI:10.1016/j.bbi.2025.03.026