DNA glycosylase Neil2 contributes to genomic responses in the spleen during clinical prion disease.

Katja Scheffler, Clara M O Jalland, Sylvie L Benestad, Torfinn Moldal, Cecilie Ersdal, Gjermund Gunnes, Rajikala Suganthan, Magnar Bjørås, Michael A Tranulis

Free radical biology & medicine 2020 May 20

filter terms:

The DNA glycosylase Neil2 is a member of the base excision repair (BER) family of enzymes, which are important for repair of oxidative DNA damage. Specifically, Neil2 participates in repair of oxidized bases in single-stranded DNA of transcriptionally active genes. Mice with genetic ablation of Neil2 (Neil2-/-) display no overt phenotypes, but an age-dependent accumulation of oxidative DNA damage and increased inflammatory responsiveness. In young mice intra-cerebrally inoculated with prions, vigorous prion propagation starts rapidly in the germinal follicles of the spleen due to inoculum spillover. Here, we compare experimental prion disease in Neil2-/- mice with that in wild-type mice at disease onset and end-stage. Specifically, we investigated disease progression, accumulation of DNA damage, and mitochondrial respiratory complex activity in brain and spleen. We used genome-wide RNA sequencing of the spleen to compare the immune responses to prion propagation between the two groups of mice, at both onset and end-stage prion disease. The Neil2-/- mice deteriorated more rapidly than wild-type mice after onset of clinical signs. Levels of DNA damage in brain increased in both mouse groups, slightly more in the Neil2-/- mice. Transcriptome data from spleen at disease onset were similar between the mouse groups with moderate genomic responses. However, at end-stage a substantial response was evident in the wild-type mice but not in Neil2-/- mice. Our data show that Neil2 counteracts toxic signaling in clinical prion disease, and this is separate from gross pathological manifestations and PrPSc accumulation. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Katja Scheffler, Clara M O Jalland, Sylvie L Benestad, Torfinn Moldal, Cecilie Ersdal, Gjermund Gunnes, Rajikala Suganthan, Magnar Bjørås, Michael A Tranulis. DNA glycosylase Neil2 contributes to genomic responses in the spleen during clinical prion disease. Free radical biology & medicine. 2020 May 20;152:348-354