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Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia.

ABSTRACT: Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c.391G > A [p.A131T], MAF 7.79 × 10^-5 and c.2702T > G [p.V901G], MAF 2.51 × 10^-3). The CSPG4^A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4^V901G mutation was nominally enriched in cases (11 cases vs. 3 controls, P = 0.026, OR 3.77, 95% CI 1.05-13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4^A131T mutation carriers exhibited abnormal post-translational processing (P = 0.029), subcellular localization of mutant NG2 (P = 0.007), as well as aberrant cellular morphology (P = 3.0 × 10^-8), viability (P = 8.9 × 10^-7), and myelination potential (P = 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4^A131T (P = 0.006) and CSPG4^V901G (P = 3.4 × 10^-4) mutations. Finally, in vivo diffusion tensor imaging of CSPG4^A131T mutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P = 2.2 × 10^-5). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia.

SUBMITTER: de Vrij FM

PROVIDER: S-EPMC6755981 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Oligodendrocytes are the glial cells responsible for the formation of the myelin sheath around axons. During neurodevelopment, oligodendrocytes undergo maturation and differentiation, and later remyelination in adulthood. Abnormalities in these processes have been associated with behavioral and cognitive dysfunctions and the development of various mental illnesses like schizophrenia. Several studies have implicated oligodendrocyte dysfunction and myelin abnormalities in the disorder, together with altered expression of myelin-related genes such as Olig2, CNP, and NRG1. However, the molecular mechanisms subjacent of these alterations remain elusive. Schizophrenia is a severe, chronic psychiatric disorder affecting more than 23 million individuals worldwide and its symptoms usually appear at the beginning of adulthood. Currently, the major therapeutic strategy for schizophrenia relies on the use of antipsychotics. Despite their widespread use, the effects of antipsychotics on glial cells, especially oligodendrocytes, remain unclear. Thus, in this review we highlight the current knowledge regarding oligodendrocyte dysfunction in schizophrenia, compiling data from (epi)genetic studies and up-to-date models to investigate the role of oligodendrocytes in the disorder. In addition, we examined potential targets currently investigated for the improvement of schizophrenia symptoms. Research in this area has been investigating potential beneficial compounds, including the D-amino acids D-aspartate and D-serine, that act as NMDA receptor agonists, modulating the glutamatergic signaling; the antioxidant N-acetylcysteine, a precursor in the synthesis of glutathione, protecting against the redox imbalance; as well as lithium, an inhibitor of glycogen synthase kinase 3? (GSK3?) signaling, contributing to oligodendrocyte survival and functioning. In conclusion, there is strong evidence linking oligodendrocyte dysfunction to the development of schizophrenia. Hence, a better understanding of oligodendrocyte differentiation, as well as the effects of antipsychotic medication in these cells, could have potential implications for understanding the development of schizophrenia and finding new targets for drug development.

Project description:Oligodendrocytes myelinate axons and form myelin sheaths in the central nervous system. The development of therapies for demyelinating diseases, including multiple sclerosis and leukodystrophies, is a challenge because the pathogenic mechanisms of disease remain poorly understood. Primate pluripotent stem cell-derived oligodendrocytes are expected to help elucidate the molecular pathogenesis of these diseases. Oligodendrocytes have been successfully differentiated from human pluripotent stem cells. However, it is challenging to prepare large amounts of oligodendrocytes over a short amount of time because of manipulation difficulties under conventional primate pluripotent stem cell culture methods. We developed a proprietary dissociated monolayer and feeder-free culture system to handle pluripotent stem cell cultures. Because the dissociated monolayer and feeder-free culture system improves the quality and growth of primate pluripotent stem cells, these cells could potentially be differentiated into any desired functional cells and consistently cultured in large-scale conditions. In the current study, oligodendrocyte progenitor cells and mature oligodendrocytes were generated within three months from monkey embryonic stem cells. The embryonic stem cell-derived oligodendrocytes exhibited in vitro myelinogenic potency with rat dorsal root ganglion neurons. Additionally, the transplanted oligodendrocyte progenitor cells differentiated into myelin basic protein-positive mature oligodendrocytes in the mouse corpus callosum. This preparative method was used for human induced pluripotent stem cells, which were also successfully differentiated into oligodendrocyte progenitor cells and mature oligodendrocytes that were capable of myelinating rat dorsal root ganglion neurons. Moreover, it was possible to freeze, thaw, and successfully re-culture the differentiating cells. These results showed that embryonic stem cells and human induced pluripotent stem cells maintained in a dissociated monolayer and feeder-free culture system have the potential to generate oligodendrocyte progenitor cells and mature oligodendrocytes in vitro and in vivo. This culture method could be applied to prepare large amounts of oligodendrocyte progenitor cells and mature oligodendrocytes in a relatively short amount of time.

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Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia.

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