The Schizophrenia-Associated Gene, CSMD1, Encodes a Brain-Specific Complement Inhibitor
Baum, Matthew L.
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CitationBaum, Matthew L. 2018. The Schizophrenia-Associated Gene, CSMD1, Encodes a Brain-Specific Complement Inhibitor. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractFour threads of biological observation have recently converged into a theory in which over-exuberant synaptic pruning contributes to the pathogenesis of Schizophrenia: 1) post mortem, there is a reduced number of dendritic spines in the frontal cortex of individuals with Schizophrenia, 2) the disorder has a characteristic onset in late adolescence, a normal critical period for pruning and thinning of the frontal cortex, 3) clinical high risk young people who convert to psychosis have an accelerated rate of frontal cortex thinning coincident with psychosis onset, 4) human genetics strongly implicates hyper-function of synaptic pruning machinery in disease risk – specifically, disease risk increases with brain expression and genomic copy number of complement component 4 (C4), a member of a cascade of immune molecules repurposed in the brain to promote the sculpting of circuits. To orthogonally test a pruning hypothesis of schizophrenia, we sought to investigate whether an inhibitor of this pruning machinery is also implicated in disease risk. Genetics, Structural biology, in vitro biochemistry, and expression suggested that the large transmembrane protein encoded by the giant gene, CSMD1 (CUB and Sushi Multiple Domains 1), could be such a disease associated complement inhibitor: a) a genome-wide significant association signal localizes to CSMD1, b) the gene encodes a protein composed almost entirely of protein domains conserved in inhibitors/regulators of the complement cascade, i.e., CUB (Complement, Urchin-EGF, Bone-Morphogenic protein) and Sushi (aka CCP or Complement Control Proteins) domains, c) protein fragments of CSMD1 can directly and indirectly inhibit the activation of C4 and C3 in vitro, d) CSMD1 mRNA is brain-enriched. Despite these intriguing observations, however, little was known about the about the normal functions of CSMD1 in neural tissues. Here, we show that CSMD1 protein is highly brain enriched, is most pronounced in cortex, present at synapses, and is expressed predominantly by neurons. Using a human stem cell line and a mouse each genetically lacking CSMD1, we present evidence that CSMD1 regulates complement activation on neural cells and in vivo, and that loss of Csmd1 abrogates the development of a complement-and-pruning-dependent neural circuit. Together, these data corroborate CSMD1 as a brain-specific complement inhibitor.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41121210
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