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: | 06 Aug 2025 21:26 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/177190 |
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