The schizophrenia-associated gene CSMD1 encodes a complement classical pathway inhibitor predominantly expressed by astrocytes and at synapses in mice and humans

Byrne, Robert A.J., Nimmo, Jacqui, Torvell, Megan, Carpanini, Sarah M., Daskoulidou, Nikoleta, Hughes, Timothy R. ORCID: https://orcid.org/0000-0003-2348-3490, Noble, Lucy V., Veteleanu, Aurora, Watkins, Lewis M., Zelek, Wioleta M., O'Donovan, Michael C. ORCID: https://orcid.org/0000-0001-7073-2379 and Morgan, Bryan Paul ORCID: https://orcid.org/0000-0003-4075-7676 2025. The schizophrenia-associated gene CSMD1 encodes a complement classical pathway inhibitor predominantly expressed by astrocytes and at synapses in mice and humans. Brain, Behavior, and Immunity 127 , pp. 287-302. 10.1016/j.bbi.2025.03.026

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine Research Institutes & Centres > The Hodge Centre for Neuroppsychiatric Immunology (HCNI)
Publisher:	Elsevier
ISSN:	0889-1591
Date of First Compliant Deposit:	26 March 2025
Date of Acceptance:	17 March 2025
Last Modified:	02 Apr 2025 11:21
URI:	https://orca.cardiff.ac.uk/id/eprint/177190

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