Endogenous retroviruses are associated with hippocampus-based memory impairment.

Abstract

Retrotransposons compose a staggering 40% of the mammalian genome. Among them, endogenous retroviruses (ERV) represent sequences that closely resemble the proviruses created from exogenous retroviral infection. ERVs make up 8 to 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 2 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, PCR, immunohistochemistry, and western blot assays). Mice lacking mitochondrial antiviral-signaling protein (MAVS) and mice lacking stimulator of IFN genes protein (STING), 2 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. ERV activation was accompanied by significant hippocampus-related memory impairment in both models. Notably, the 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 molecular target for strategies aimed at attenuating retroviral element sensing, via MAVS, to treat dementia and neuropsychiatric disorders.

• Authors: Roman Sankowski, Joshua J Strohl, Tomás S Huerta, Elham Nasiri, Andrea N Mazzarello, Cristina D'Abramo, Kai Fan Cheng, Ori Staszewski, Marco Prinz, Patricio T Huerta, Yousef Al-Abed
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 116 Issue 51 Pg. 25982-25990 (12 17 2019) ISSN: 1091-6490 [Electronic] United States
• PMID: 31792184 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2019 the Author(s). Published by PNAS.

Chemical References

• Adaptor Proteins, Signal Transducing
• DNA Transposable Elements
• Gene Products, gag
• IPS-1 protein, mouse
• Membrane Proteins
• Sting1 protein, mouse
• Streptozocin

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Animals
• Behavior, Animal
• Brain (pathology)
• Cognitive Dysfunction
• DNA Transposable Elements
• Disease Models, Animal
• Endogenous Retroviruses (genetics, physiology)
• Gene Expression Regulation
• Gene Products, gag
• Hippocampus (drug effects, virology)
• Learning
• Male
• Membrane Proteins (metabolism)
• Memory
• Memory Disorders (genetics, metabolism, psychology, virology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Streptozocin (pharmacology)