The key role of Protocadherin in the pathogenesis of schizophrenia
Schizophrenia (SCZ) is a highly hereditary mental disorder, compared to “a tumor in mental diseases”.However, the pathogenesis of schizophrenia remains unclear, which brings great difficulties to clinical diagnosis and treatment.Revealing the pathogenesis and exploring the effective treatment targets are impossibly urgent.The genome-wide association study (GWAS) of patients with schizophrenia based on large samples has identified 108 SCZ risk genomic loci, which defines its high value of reference for exploring the pathogenesis of SCZ.However, to clarify which risk genes and how they contribute to SCZ are incredibly challenging tasks.In this study, a patient-specific iPSC model was established and we demonstrated that such patient-derived iPSCs were able to differentiate into cortical interneurons of developmental stage with neuronal physiological activity. More encouragingly, it can be integrated into the host neural network after transplantation.At the same time, we found that Protocadherin Alpha (PCDHA) was abnormally expressed in SCZ interneurons, causing defects in the number of processes, branches and synapses of interneurons. Through transplantation of SCZ interneurons into mice and PCDHA knockout mouse models as well as brain tissue samples from SCZ patients, we illustrated the key function of PCDHA in interneurons’ morphology. These findings uncovered an important mechanism by which the risk gene PCDHA contributes to the development of schizophrenia.
Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia.Nature Neuroscience2019,22(2), 229-242.
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