A role for the centrosome has been suggested in the pathology of major mental illnesses, especially schizophrenia (SZ).
To show that pericentriolar material-1 protein (PCM1) forms a complex at the centrosome with Disrupted-In-Schizophrenia-1 (DISC1) and Bardet-Biedl syndrome-4 protein (BBS4), which provides a crucial pathway for cortical development associated with the pathology of SZ. To identify mutations in the PCM1 gene in a SZ population.
Interaction of DISC1, PCM1, and BBS proteins was assessed by immunofluorescent staining and co-immunoprecipitation. Effects of PCM1, DISC1, and BBS on centrosomal functions and corticogenesis in vivo were tested by RNAi. PCM1 gene was examined by sequencing 39 exons and flanking splice sites.
Setting and Patients
Thirty-two probands with SZ from families that had excess allele sharing among affected individuals at 8p22, and 219 Caucasian controls.
Main Outcome Measures
Protein interaction and recruitment at the centrosome in cells; neuronal migration in the cerebral cortex; variant discovery in PCM1 in SZ patients.
PCM1 forms a complex with DISC1 and BBS4 through discrete binding domains in each protein. DISC1 and BBS4 are required for targeting PCM1 and other cargo proteins, such as ninein, to the centrosome in a synergistic manner. In the developing cerebral cortex, suppression of PCM1 leads to neuronal migration defects, which are phenocopied by the suppression of either DISC1 or BBS4, and are exacerbated by the concomitant suppression of both. Furtheremore, a nonsense mutation that segregates with schizophrenia-spectrum psychosis is found in one family.
Our data further support for the role of centrosomal proteins in cortical development and suggest that perturbation of centrosomal function contributes to the development of mental diseases including SZ.