Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the retroviral/retroposon hypothesis of schizophrenia by generating sequences with PCR primers based on a retroviral sequence recovered by Yee et al. [1998: Schizophr Res 29:92] from a cDNA library from postmortem brain tissue from an individual with psychosis in a genomic region (Xq21.3) that has been tentatively linked to schizophrenia and schizoaffective disorder by Laval et al. [1998: Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:420-427]. Within the block of homology with Yp that was generated by a transposition between the chimpanzee and Homo sapiens we find two sequences, HS307 and HS408, with a high degree of homology to but not identity with the schizophrenic brain cDNA. The closest match of these three sequences is to a family of retroposons, that has evolved from the HERV-K family of endogenous retroviruses, some members of which (e.g., SINE-R.C2) appear to be specific to the human genome. This element has been reported as a cause of Fukuyama-type muscular dystrophy [Kobayashi et al., 1998: Nature 394:388-392]. Such retroposons, as agents of change in the human genome, provide a strategy for investigating pathogenesis. On account of their genomic location in a region that has been subject to change in the course of hominid evolution, and that may have a relationship to psychosis and/or cerebral asymmetry, we conclude that these particular insertions deserve further investigation.
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PMID:SINE-R.C2 (a Homo sapiens specific retroposon) is homologous to CDNA from postmortem brain in schizophrenia and to two loci in the Xq21.3/Yp block linked to handedness and psychosis. 1049 Jul 17

Genetic studies of neuropsychiatric disorders have often produced conflicting results, which might partly result from the involvement of epigenetic modifications. We intended to explore the possible implication of DNA methylation and human endogenous retroviruses (HERVs) in neuropsychiatric disorders. In the present study, we identified two HERV loci that are expected to retain the transcriptional activity in the brain. One was located on chromosome 1q21-q22 and the other on 22q12. Interestingly, these regions were overlapped with or included in those of schizophrenia-susceptible loci, SCZD9 and SCZD4, respectively. Particularly, the HERV on 22q12 was located in the opposite direction 4 kb downstream of the Synapsin III gene. These HERV loci could afford clear targets for methylation and expression analyses in postmortem brains of patients with psychiatric disorders such as schizophrenia. In addition, we confirmed our previous finding that only a few of particular HERV-K loci were activated among a number of highly homologous loci in teratocarcinoma cell lines. These activated loci included ones common to all teratocarcinoma cell lines analyzed and depending on their male or female origin.
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PMID:Human endogenous retroviruses with transcriptional potential in the brain. 1456 40

The detection and identification of retroviral transcripts in brain samples, cerebrospinal fluid, and plasma of individuals with recent-onset schizophrenia and schizoaffective disorders suggest that activation or upregulation of distinct human endogenous retroviruses (HERVs) may play a role in the etiopathogenesis of neuropsychiatric diseases. To test this hypothesis, we performed a comprehensive microarray-based analysis of HERV transcriptional activity in human brains. We investigated 50 representative members of 20 HERV families in a total of 215 brain samples derived from individuals with schizophrenia or bipolar disorders and matched controls. A characteristic brain-specific retroviral activity profile was found that consists of members of the class I families HERV-E, HERV-F, and ERV9 and members of HERV-K taxa. In addition to these constitutively expressed HERVs, a number of differentially active HERV elements were identified in all brain samples independent of the disease pattern that may reflect differences in the genetic background of the tested individuals. Only a subgroup of the HML-2 family (HERV-K10) was significantly overrepresented in both bipolar-disorder- and schizophrenia-associated samples compared to healthy brains, suggesting a potential association with disease. Real-time PCR analysis of HERV env transcripts with coding capacity potentially involved in neuroinflammatory conditions revealed that env expression of HERV-W, HERV-FRD, and HML-2 remains unaffected regardless of the clinical picture. Our data suggest that HERV transcription in brains is weakly correlated with schizophrenia and related diseases but may be influenced by the individual genetic background, brain-infiltrating immune cells, or medical treatment.
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PMID:Human endogenous retrovirus expression profiles in samples from brains of patients with schizophrenia and bipolar disorders. 1610 41

Retroviruses are implicated in the pathogenesis of schizophrenia. Human endogenous retrovirus type K115 (HERV-K115) is a full-length, potentially transcriptional retrovirus and is also polymorphic. We investigated the frequency of HERV-K115 in Japanese schizophrenia patients and healthy controls. No difference was found in the frequency between patients and controls (8.4% versus 9.4%, respectively). However, a marginal difference was observed in age at onset between the HERV-K positive and negative patients (p=0.057). The HERV-K115 insertion appeared to be more frequent in patients with younger onset than those with later onset. These results preliminarily suggest that HERV-K115 may not be associated with schizophrenia in general, but that it could play a partial role in early precipitation of the disease.
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PMID:Insertional polymorphism of endogenous retrovirus HERV-K115 in schizophrenia. 1700 49

In humans, exogenous retroviruses are known to cause immunodeficiency and neurological disease. While endogenous retroviruses are firmly established pathogens in other species, the human endogenous retroviruses (HERVs) may well be considered as emerging pathogens. HERVs also exhibit complex interactions with exogenous retroviruses and herpesviruses. Two neurological disorders in particular are associated with HERVs: multiple sclerosis (MS) and schizophrenia. HERV-H/F and HERV-W are specifically activated both in the circulation and the central nervous system (CNS) in a majority of MS patients, and particularly, the envelopes (env transcription and Env proteins) appear strongly associated with disease activity. Interferon beta (IFN-beta) therapy is well-established for MS. IFN-beta is also known to have anti-retroviral activities toward exogenous retroviruses (HIV and HTLV-I). New reports show that IFN-beta also mediate down-regulation of HERV-H/F and HERV-W in MS patients. HERV-W and HERV-K transcription (gag and pol) appears, to some extent, to be up-regulated in the circulation and the CNS of patients with schizophrenia. The expression of anti-HERV-W Gag reactive epitopes is reported to be down-regulated in the brain but up-regulated in the blood from schizophrenia patients. The pathogenic potential of HERVs certainly merits further studies.
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PMID:HERVs in neuropathogenesis. 2042 98

Human endogenous retroviruses (HERVs) have been associated with various neurological and neuropsychiatric disorders. Transcripts and proteins of at least three HERV groups, HERV-W, ERV9 and HERV-K(HML-2) have been detected repeatedly in brain samples or cerebrospinal fluid of patients with schizophrenia suggesting that alterations in HERV activity may play a role in etiopathogenesis. Current therapies otherwise include neuroleptics and/or antidepressants that may induce epigenetic alterations and thus influence HERV expression. To investigate the effects of these drugs on HERV transcriptional activity, HERV expression profiles of a broad range of human brain cell lines treated with valproic acid (VPA), haloperidol, risperidone, and clozapine were analyzed using a retrovirus-specific microarray and qRT-PCR. Investigation of 52 HERV subgroups revealed upregulation of several class I and class II HERV elements by VPA in a dose-dependent manner. The strongest effect was observed on HERV-W and ERV9 groups in the human glioblastoma cell lines SK-N-SH and SK-N-MC, respectively. The transcript level of HERV-K(HML-2) elements was not influenced. Transcription of HERV-W, ERV9 and HERV-K(HML-2) taxa was further quantified in postmortem brain samples of patients with schizophrenia, bipolar disorders and a healthy control group with regard to their medication. Patients with schizophrenia showed a significantly higher HERV-W transcription associated with VPA treatment. However in case of ERV9, enhanced transcript levels could not be explained solely by VPA treatment, since a slight increase was also found in untreated patients compared to healthy controls. HERV-K(HML-2) elements appeared to be upregulated in some patients with bipolar disorders independent from medication. In conclusion, these results suggest that antipsychotic medication may contribute to increased expression of distinct HERV taxa in patients with neuropsychiatric diseases.
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PMID:Influence of antipsychotic drugs on human endogenous retrovirus (HERV) transcription in brain cells. 2225 75

Endogenous retroviruses are pathogenic - in other species than the human. Disease associations for Human Endogenous RetroViruses (HERVs) are emerging, but so far an unequivocal pathogenetic cause-effect relationship has not been established. A role for HERVs has been proposed in neurological and neuropsychiatric diseases as diverse as multiple sclerosis (MS) and schizophrenia (SCZ). Particularly for MS, many aspects of the activation and involvement of specific HERV families (HERV-H/F and HERV-W/MSRV) have been reported, both for cells in the circulation and in the central nervous system. Notably envelope genes and their gene products (Envs) appear strongly associated with the disease. For SCZ, for ALS, and for HIV-associated dementia (HAD), indications are accumulating for involvement of the HERV-K family, and also HERV-H/F and/or HERV-W. Activation is reasonably a prerequisite for causality as most HERV sequences remain quiescent in non-pathological conditions, so the importance of regulatory pathways and epigenetics involved in regulating HERV activation, derepression, and also involvement of retroviral restriction factors, is emerging. HERV-directed antiretrovirals have potential as novel therapeutic paradigms in neurologic disease, particularly in MS. The possible protective or ameliorative effects of antiretroviral therapy in MS are substantiated by reports that treatment of HIV infection may be associated with a significantly decreased risk of MS. Further studies of HERVs, their role in neurologic diseases, and their potential as therapeutic targets are essential.
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PMID:Human endogenous retroviruses in neurologic disease. 2681 66

Human endogenous retroviruses (HERV) have been widely associated with schizophrenia etiology. Aberrant epigenetic processes may play a role in the etiology of schizophrenia. In this study, we tested whether schizophrenia patients at different stages of illness might present alterations in the levels of HERV-K methylation. We recruited 49 first-episode schizophrenia (FES) patients with 47 age- and sex-matched healthy controls (HCs), and 100 multi-episode schizophrenia (MES) patients with 50 age- and sex-matched HCs. Based on the Schedule for Deficit Schizophrenia, patients with MES were also divided into two subgroups: deficit (D-SCZ) and non-deficit schizophrenia (ND-SCZ). DNA methylation levels of HERV-K sequences were examined in peripheral blood leukocytes. We found significantly lower levels of HERV-K methylation in FES patients compared to HCs. Patients with MES and matched HCs had similar levels of HERV-K methylation. There was a significant positive correlation between chlorpromazine equivalent dosage and HERV-K methylation levels in MES patients, but not in FES individuals. No significant differences in HERV-K methylation levels between D-SCZ and ND-SCZ as well as HCs were found. Our results indicate lower HERV-K methylation levels at early stages of schizophrenia. This difference might normalize with subsequent exacerbations of schizophrenia, likely due to the effects of antipsychotics.
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PMID:First-episode schizophrenia is associated with a reduction of HERV-K methylation in peripheral blood. 3053 69

Human endogenous retroviruses (HERVs) are ancient retroviral elements, which invaded the human germ line several million years ago. Subsequent retrotransposition events amplified these sequences, resulting in approximately 8% of the human genome being composed of HERV sequences today. These genetic elements, normally dormant within human genomes, can be (re)-activated by environmental factors such as infections with other viruses, leading to the expression of viral proteins and, in some instances, even to viral particle production. Several studies have shown that the expression of these retroviral elements correlates with the onset and progression of neurological diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Further studies provided evidence on additional roles for HERVs in schizophrenia (SCZ). Since these diseases are still not well understood, HERVs might constitute a new category of pathogenic components that could significantly change our understanding of these pathologies. Moreover, knowledge about their mode of action might also help to develop novel and more powerful approaches for the treatment of these complex diseases. Therefore, the main scope of this review is a description of the current knowledge on the involvement of HERV-W and HERV-K in neurological disease specifically focusing on the effects they exert on neural cells of the central nervous system.
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PMID:Neural Cell Responses Upon Exposure to Human Endogenous Retroviruses. 3135 94