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 ). 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 posttranslational 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 noncarrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4 A131T (P = 0.006) and CSPG4) 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.

Oligodendrocytes as A New Therapeutic Target in Schizophrenia: From Histopathological Findings to Neuron-Oligodendrocyte Interaction

“…Carrier-derived hiPSC neurons were not pathological, underlining the oligodendroglial cell-autonomous effect of the CSPG4 mutations. Remarkably, DTI-detectable impairments of white matter integrity were found in affected mutation carriers but not in their unaffected siblings or the general population [100]. In a pioneer study by Windrem and colleagues [101] in hiPSC from patients with childhood-onset SZ, glial precursor cells, which could mature into both oligodendroglial and astroglial lineage cells, showed altered transcriptomic signatures and impaired astroglial maturation and hypomyelination.…”

“…Expression of the SZ risk gene FEZ1 is regulated by SZ-relevant pathways, and knockdown of FEZ1 in murine and human iPSC-derived oligodendroglial cells was found to disturb oligodendrocyte development [99]. A family-based approach used hiPSC oligodendrocyte progenitor cells to investigate the contribution to SZ of two rare missense mutations in CSPG4, which codes for NG2, a prominent marker for proliferating oligodendrocyte progenitor cells [100]. The study found that hiPSC oligodendrocyte progenitor cells with one of the CSPG4 mutations showed dysregulated posttranslational processing, subcellular localization of mutant NG2, and impaired oligodendrocyte progenitor cell survival, with reduced differentiation to mature oligodendrocytes.…”

“…However, they have several limitations. Family-based studies investigated single, rare SZ variants with large effects [99,100], but the genetic reality of most SZ patients is a polygenic accumulation of common variants with low individual effect sizes [83]. Windrem et al studied glial progenitor cells (GPCs) in a very limited number of individuals with childhood-onset SZ (a rare disorder) with a very time-consuming experimental protocol (>200 days to generate GPCs) [101], which limits subsequent functional analysis or rescue experiments.…”

Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte–myelin dysfunction

“…Furthermore, given the limitations of animal models of neuropsychiatric disorders, complementary models of human glia in the context of MMI are particularly necessary. Indeed, recent studies using patient derived iPS cells have shown impaired glial maturation suggesting a causal link with SZ [23,24].…”

Exploring landscapes of brain morphogenesis with organoids

“…Several studies have already demonstrated the utility of brain organoids and other in vitro neural models to identify disease mechanisms, such as in the case of genetic and acquired microcephaly. Along these lines, work presented by Silvia Cappello, Marisa Karow, Femke De Vrij and Andras Lakatos (de Vrij et al, 2018;Tyzack et al, 2017) focused on human conditions for which in vitro neural models have enormous potential.…”