Human endogenous retrovirus expression profiles in samples from brains of patients with schizophrenia and bipolar disorders - PubMed (original) (raw)

Comparative Study

Human endogenous retrovirus expression profiles in samples from brains of patients with schizophrenia and bipolar disorders

Oliver Frank et al. J Virol. 2005 Sep.

Abstract

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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Figures

FIG. 1.

FIG. 1.

Validation of the animal retrovirus-specific microarray (pet chip). Genomic DNAs (100 ng) derived from avian (Gallus gallus domesticus) and mammalian (Rattus rattus, Mus musculus, Felis catus, Sus scrofa domestica, and Papio hamadryas) genera were amplified with primers using the standardized amplification protocol. The names and corresponding grid locations of animal retrovirus-specific oligonucleotides (capture probes) are shown in the top panel. Grid locators represented by a spotted Cy3-labeled arbitrary oligonucleotide are designated Cy3. For the origins and identities of all capture probes, see Table 2.

FIG. 2.

FIG. 2.

Alignment of false-color chip data sets corresponding to HERV class I, II, and III transcriptional activities observed in 10 different brain regions of a healthy human brain (A) and in prefrontal-cortex brain samples from 35 healthy individuals (B) by HERV microarray hybridization. A housekeeping-gene panel served as an internal control. For the origins and identities of the dots, see Table 1. QRT-PCR was performed for a subset of seven samples indicated by red numbers and a subset of three HERV elements (HERV-W, HERV-FRD, and HML-2) and the housekeeping gene HPRT, marked by red asterisks. HERV elements representing the brain-specific HERV activity profile are indicated by red boxes (bottom line).

FIG. 3.

FIG. 3.

Incidences of HERV transcripts in 105 brain RNA samples. Ubiquitously active HERVs are marked with black boxes (incidence, 33 to 35/35), and differentially active (incidence, 3 to 32/35) and inactive (incidence, 0 to 2/35) HERV elements are depicted by gray and white boxes, respectively. “-” means that the P value was not significant in Fisher's exact test.

FIG. 4.

FIG. 4.

Relative quantification of HERV env transcriptional activity by QRT-PCR. Transcriptional activities of HML-2, HERV-W, and HERV-FRD were analyzed in a subset of seven healthy (NC) and seven schizophrenia-derived (SCZ) brain samples. The relative abundance of HERV transcripts in each sample was normalized by HPRT levels and represents the mean value of at least triplicate experiments.

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