ERVWE1 Reduces Hippocampal Neuron Density and Impairs Dendritic Spine Morphology through Inhibiting Wnt/JNK Non-Canonical Pathway via miR-141-3p in Schizophrenia

Abstract

Human endogenous retroviruses (HERVs) are remnants of ancestral germline infections by exogenous retroviruses. Human endogenous retroviruses W family envelope gene (HERV-W env, also called ERVWE1), located on chromosome 7q21-22, encodes an envelope glycoprotein from the HERV-W family. Mounting evidence suggests that aberrant expression of ERVWE1 involves the etiology of schizophrenia. Moreover, the genetic and morphological studies indicate that dendritic spine deficits may contribute to the onset of schizophrenia. Here, we reported that ERVWE1 changed the density and morphology of the dendritic spine through inhibiting Wingless-type (Wnt)/c-Jun N-terminal kinases (JNK) non-canonical pathway via miR-141-3p in schizophrenia. In this paper, we found elevated levels of miR-141-3p and a significant positive correlation with ERVWE1 in schizophrenia. Moreover, serum Wnt5a and actin-related protein 2 (Arp2) levels decreased and demonstrated a significant negative correlation with ERVWE1 in schizophrenia. In vitro experiments disclosed that ERVWE1 up-regulated miR-141-3p expression by interacting with transcription factor (TF) Yin Yang 1 (YY1). YY1 modulated miR-141-3p expression by binding to its promoter. The luciferase assay revealed that YY1 enhanced the promoter activity of miR-141-3p. Using the miRNA target prediction databases and luciferase reporter assays, we demonstrated that miR-141-3p targeted Wnt5a at its 3’ untranslated region (3′ UTR). Furthermore, ERVWE1 suppressed the expression of Arp2 through non-canonical pathway, Wnt5a/JNK signaling pathway. In addition, ERVWE1 inhibited Wnt5a/JNK/Arp2 signal pathway through miR-141-3p. Finally, functional assays showed that ERVWE1 induced the abnormalities in hippocampal neuron morphology and spine density through inhibiting Wnt/JNK non-canonical pathway via miR-141-3p in schizophrenia. Our findings indicated that miR-141-3p, Wnt5a, and Arp2 might be potential clinical blood-based biomarkers or therapeutic targets for schizophrenia. Our work also provided new insight into the role of ERVWE1 in schizophrenia pathogenesis.

Ancient dormant virus remnant ERVW-1 drives ferroptosis via degradation of GPX4 and SLC3A2 in schizophrenia

“…ELISA of blood samples revealed higher ERVW-1 levels in schizophrenia patients ( Fig. 2 D), consistent with our previous study ( Huang et al., 2011 ; Li et al., 2023 ; Wang et al., 2018 ; Wu et al., 2023 ; Xia et al., 2021 ; Yan et al., 2022 ; Yao et al., 2023 ). Furthermore, Spearman's analysis showed that ERVW-1 negatively correlated with GPX4 ( Fig.…”

“…HERVs contribute to development of various disorders through multiple mechanisms ( Geis et al., 2020 ; Zhang et al., 2022 ), such as assembling viral particles ( Wang et al., 2018 ), generating HERV-derived lncRNAs ( Zhou et al., 2019 ) and dsRNAs ( Canadas et al., 2018 ), acting as promoters or enhancers to regulate cellular gene expression through LTR cis -regulatory element ( Yu et al., 2013 ), or encoding viral proteins to regulate host cell signaling networks ( Li et al., 2023 ; Wang et al., 2018 ; Wu et al., 2023 ; Xia et al., 2021 ; Yan et al., 2022 ; Yao et al., 2023 ). Abnormal expression of ERVW-1 has been linked to schizophrenia ( Huang et al., 2011 ; Xia et al., 2021 ; Yan et al., 2022 ), and further studies have shown that ERVW-1 induces inflammatory abnormalities, including promoting NO release ( Xiao et al., 2017 ), activating TLR3 signaling pathway ( Wang et al., 2018 , 2021 ), promoting cytotoxic T lymphocyte (CTL) responses of glial cells ( Tu et al., 2017 ), and inducing innate immune activation by upregulating IFN-β, thereby mediating neuronal apoptosis ( Li et al., 2023 ).…”

“…Emerging evidence indicates that ERVW-1 is associated with a variety of diseases, including autoimmune diseases ( Mameli et al., 2007 ), cancers ( Yu et al., 2014 ; Zhou et al., 2021 ), and neuropsychiatric disorders ( Kury et al., 2018 ; Wang et al., 2018 ). Notably, previous research has shown that ERVW-1 is abnormally elevated in patients with schizophrenia ( Huang et al., 2011 ; Li et al., 2023 ; Wu et al., 2023 ; Xia et al., 2021 ; Yan et al., 2022 ; Yao et al., 2023 ).…”

“…human cytomegalovirus ( Illescas-Montes et al., 2019 ) and hepatitis B virus ( Liu et al., 2017 )), and internal factors such as aging-associated processes ( Nevalainen et al., 2018 ) and epigenetics changes ( Garcia-Montojo et al., 2018 ). Activated HERVs may be involved in certain diseases, such as certain cancers ( Jansz et al., 2021 ; Yu et al., 2013 ), autoimmune diseases ( Posso-Osorio et al., 2021 ), and neuropsychiatric disorders ( Li et al., 2023 ; Yao et al., 2023 ).…”

HERVs and Cancer—A Comprehensive Review of the Relationship of Human Endogenous Retroviruses and Human Cancers

“…As the first treatment targeting a human endogenous retrovirus (HERV) protein enters into phase III clinical trials to combat multiple sclerosis (MS) progression [ 1 ], HERVs are becoming increasingly promising targets in cancer diagnostics and therapies. Previously, HERVs have been identified as involved in the progression of complex diseases such as MS [ 1 , 2 ], schizophrenia [ 3 , 4 ], and type 1 diabetes [ 5 , 6 ]. Lessons learned from these phenotypes have illuminated the potential for HERVs to impact human cancer development and treatment options.…”