Abstract
The Wnt signaling pathway plays a crucial role in neurodevelopment and in regulating the function and structure of the adult nervous system. Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental disorders with evidence of subtle neurodevelopmental, structural and functional neuronal abnormalities. We aimed to elucidate the role of aberrant regulation of the Wnt system in these disorders by evaluating plasma levels of secreted Wnt modulators in patients (SCZ = 551 and BD = 246) and healthy controls (HCs = 639) using enzyme immune-assay. We also investigated the expression of 141 Wnt-related genes in whole blood in a subsample (SCZ = 338, BD = 241, and HCs = 263) using microarray analysis. Both SCZ and BD had dysregulated mRNA expression of Wnt-related genes favoring attenuated canonical (beta-catenin-dependent) signaling, and there were also indices of enhanced non-canonical Wnt signaling. In particular, FZD7, which may activate all Wnt pathways, but favors non-canonical signaling, and NFATc3, a downstream transcription factor and readout of the non-canonical Wnt/Ca2+ pathway, were significantly increased in SCZ and BD (p < 3 × 10−4). Furthermore, patients had lower plasma levels of soluble dickkopf 1 and sclerostin (p < 0.01) compared with HC. Our findings suggest that SCZ and BD are characterized by abnormal Wnt gene expression and plasma protein levels, and we propose that drugs targeting the Wnt pathway may have a role in the treatment of severe mental disorders.
Highlights
Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses that are leading causes of worldwide disability[1,2] and are associated with shortened lifespan[3,4,5]
Results are significant after Bonferroni correction if p < 0.01, and nominally significant if 0.01 < p < 0.05 M median, IQR interquartile range, SCZ schizophrenia, BD bipolar disorder, healthy controls (HCs) healthy control, DKK1 dickkopf 1, DKK3 dickkopf 3, sFRP3 secreted frizzled related protein 3, SOST sclerostin, RSPO3 R-spondin-3 *p < 0.05; **p < 0.01; ***p < 0.0003
RSPO3, we found nominally significant lower levels in SCZ, and no significant differences in BD compared to HC
Summary
Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses that are leading causes of worldwide disability[1,2] and are associated with shortened lifespan[3,4,5]. Wnt signaling pathway plays a crucial role in neural stem cell proliferation, differentiation and migration, neuroplasticity, and neurogenesis[12,13] Secreted modulators such as the dickkopf (DKKs) and the secreted frizzled related proteins (sFRPs) regulate both the canonical (βcatenin-dependent) and non-canonical (β-catenin-independent) Wnt signaling, modulating the effects of various Wnt ligands[14]. Secreted Wnt antagonists, such as DKK419, sFRP1, and FZD320,21, have been associated with brain volumes[22] and increased susceptibility to SCZ. These Wnt antagonists are located in the chromosomal region 8p, which is a genetically implicated region in neuropsychiatric disorders[18]. No studies have investigated serum levels of central secreted Wnt antagonists such as DKKs or frizzled related proteins
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