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Endogenous retroviruses are associated with hippocampus-based memory impairment

ABSTRACT: Retrotransposons comprise a staggering 40% of the mammalian genome. Among them, endogenous retroviruses (ERV) represent sequences that closely resemble the proviruses created after exogenous retroviral infection. ERVs make up 8–10% of human and mouse genomes and range from evolutionarily ancient sequences to recent acquisitions. Studies in Drosophila have provided a causal link between genomic retroviral elements and cognitive decline. However, in mammals, the role of ERVs in learning and memory remains unclear. Here, we studied two independent murine models for ERV activation: muMT strain (lacking B cells and antibody production) and intracerebroventricular injection of streptozotocin (ICVI-STZ). We conducted behavioral assessments (contextual fear memory and spatial learning), as well as gene and protein analysis (RNA sequencing and PCR assays). Mice lacking mitochondrial-antiviral-signaling protein (MAVS) and mice lacking stimulator-of-interferon-genes protein (STING), two downstream sensors of ERV activation, provided confirmation of ERV impact. We found that muMT mice and ICVI-STZ mice induced hippocampal ERV activation as shown by increased gene and protein expression of the Gag sequence of the transposable element intracisternal A-particle (IAP). ERV activation was accompanied by significant hippocampus-related memory impairment in both models. Notably, deficiency of the MAVS pathway was protective against ICVI-STZ-induced cognitive pathology. Overall, our results demonstrate that ERV activation is associated with cognitive impairment in mice. Moreover, they provide a new molecular target for strategies aimed at attenuating retroviral element sensing, via MAVS, to treat dementia and neuropsychiatric disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE137782 | GEO | 2019/12/31

REPOSITORIES: GEO

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Project description:The genome of vertebrates contains endogenous retroviruses (ERVs) that have resulted from ancestral infections by exogenous retroviruses. ERVs are germline encoded, transmitted in a Mendelian fashion and account for about 8% of the human and 9.9% of the murine genome, respectively1, 2. By spontaneous activation and reintegration ERVs may cause insertional mutagenesis and thus participate in the process of malignant transformation or progression of tumor growth3, 4. However, if the innate immune system is able to recognize and control ERVs has not yet been elucidated. Here we report that, in vitro, nucleic-acid sensing TLRs on dendritic cells are activated by retroviral RNA and DNA from infected cells in vitro. Infection of TLR competent wild type mice with murine leukemia virus (MuLV)-like ERV isolates results in non-canonical gene upregulation, independent of type I IFN. In vivo, TLR3, -7 and -9 triple deficient mice (TLR379-/-) and mice with non functional TLR3, 7 and 9 signaling due to a mutation in UNC93B develop spontaneous ERV-induced viremia. More importantly, in TLR379-/- mice ERV-induced viremia correlates with acute T cell lymphoblastic leukemia (T-ALL). Multiple independent TLR379-/- T cell leukemia lines produce infectious MuLV of endogenous origin. These cell lines display de novo retroviral integration into the Nup214 or Notch1 gene locus leading to gene dysregulation that is reminiscent of aberrant Nup214 and Notch1 expression in human T-ALLs5. Overall, our results demonstrate that in addition to their role in innate immune defense against exogenous pathogens, TLR3,-7, and -9 may be essential for the control of endogenous retroviral mediated T-cell lymphomagenesis. The data covers two data sets. The data set covers two comparisons of the expression profile from old and young TLR379-/- knockout. Spleen was taken from and old wild type (C57BL/6 background) to compare it against an old TLR379-/- knockout and also from an young wild type (C57BL/6 background) to compare it against a young TLR379-/- knockout. The second experiment includes three replicates of the wild type, the Baki-1MuLV infected C57BL/6, and the Sendai infected C57BL/6.

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Endogenous retroviruses are associated with hippocampus-based memory impairment

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