Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia

Abstract

S chizophrenia is a pervasive neuropsychiatric disease of uncertain etiology. In the United States, schizophrenia has a lifetime prevalence of greater than 1% and results in the annual expenditure of more than 65 billion dollars (1, 2). Family and adoption studies have demonstrated a significantly increased risk of schizophrenia in individuals who have a first-degree birth relative with this disease, indicating that there is a substantial genetic component in disease pathogenesis. Epidemiological studies have identified a number of environmental factors associated with the development of schizophrenia, including perinatal infections, winter-spring birth, household crowding, and upbringing in urban areas (3, 4). These genetic and environmental findings can be reconciled by the concept that the disease can result from infectious processes occurring in genetically susceptible individuals (5-8).Retroviruses have been hypothesized as one of the infectious agents involved in the pathogenesis of schizophrenia (9-11). Humans can be infected with retroviruses such as strains of human immunodeficiency virus (HIV) and human T-cell leukemia virus. These exogenous retroviruses can replicate within the central nervous system and cause neurological and psychiatric symptoms in some infected individuals. The clinical response to infection with HIV is determined, to some extent, by the genetic susceptibility of the infected individual (12-14).The human genome also contains many endogenous retroviral (HERV) elements, which have homology to known animal retroviruses. These elements probably arose from reverse transcriptase-mediated integration into the germ line of progenitors of Homo sapiens after exogenous retroviral infection. Many of the HERV sequences in the human genome are incomplete, although some full-length proviral genomic sequences have been identified. Some of these proviruses contain long open reading frames capable of encoding complete viral proteins and engendering viral particles (15)(16)(17)(18)(19)(20). The tissue-specific expression of HERVs has been associated with a number of chronic human diseases, including multiple sclerosis, diabetes, and autoimmune arthritis (21-23). We report the identification of retroviral sequences in cerebrospinal fluids (CSFs) obtained from individuals with recent-onset schizophrenia, and the differential transcriptional up-regulation of members of the HERV-W family of endogenous retroviruses in the postmortem frontal cortex of individuals with schizophrenia. Materials and Methods CSF Samples. Patients with new-onset schizophrenia.We obtained CSF samples from 35 previously healthy individuals (presenting to the Department of Psychiatry at the University of Heidelberg) with symptoms consistent with new-onset schizophrenia or schizoaffective disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. (25). These individuals had not been admitted previously to the hospital for schizophrenia and were without manifestations of acute infectious, inflammatory,...

Optimized filtering reduces the error rate in detecting genomic variants by short-read sequencing

“…Alternatively, as nonintact retroviral sequences may retain their ability to be retrotransposed by active transposons nearby during embryogenesis 32 , retrotransposon activity could have introduced the observed mosaicism. Moreover, as L1-activity has been implicated in neurological diseases 37 and retroviral RNAs have been linked to schizophrenia 38 , this SNV may confirm a potentially relevant disease mechanism contributing to schizophrenia.…”

Elevated Interleukin-6 in the Cerebrospinal Fluid of a Previously Delineated Schizophrenia Subtype

“…Viral infection could be the primary insult leading to elevation of central inflammatory cytokines, such as IL-6. Karlsson et al (2001) found retroviral sequences in the CSF of 18.6% acute-onset schizophrenics and 5% of chronic schizophrenics. No such sequences were found in the normal control group.…”

Not really identical: Epigenetic differences in monozygotic twins and implications for twin studies in psychiatry

“…These are both heavily methylated and placentally expressed endogenous retroviral-related human genome sequences. Although no direct evidence exists for any causative effect of SZRV1 and 2 on schizophrenia, these retroviruses may be abnormally expressed in the cerebrospinal fluid of individuals with recent-onset schizophrenia or schizoaffective disorder [Karlsson et al, 2001]. In one affected patient, but none of the controls, loss of DNA methylation of SZRV2 was observed [Deb-Rinker et al, 2002], suggesting that DNA methylation may restrict placentally expressed retroviral sequences as part of natural nuclear host defences against parasitic sequence elements such as viruses [Deb-Rinker et al, 2002].…”