Accelerated clinical course of prion disease in mice compromised in repair of oxidative DNA damage

Clara M.O. Jalland, Sylvie L. Benestad, Cecilie Ersdal, Katja Scheffler, Rajikala Suganthan, Yusaku Nakabeppu, Lars Eide, Magnar Bjørås, Michael A. Tranulis

Research output: Contribution to journalArticle

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Abstract

The detailed mechanisms of prion-induced neurotoxicity are largely unknown. Here, we have studied the role of DNA damage caused by reactive oxygen species in a mouse scrapie model by characterizing prion disease in the ogg1 -/- mutyh-/- double knockout, which is compromised in oxidative DNA base excision repair. Ogg1 initiates removal of the major oxidation product 8-oxoguanine (8-oxoG) in DNA, and Mutyh initiates removal of adenine that has been misincorporated opposite 8-oxoG. Our data show that the onset of clinical signs appeared unaffected by Mutyh and Ogg1 expression. However, the ogg1-/- mutyh-/- mice displayed a significantly shorter clinical phase of the disease. Thus, accumulation of oxidative DNA damage might be of particular importance in the terminal clinical phase of prion disease. The prion-induced pathology and lesion profile were similar between knockout mice and controls. The fragmentation pattern of protease-resistant PrP as revealed in Western blots was also identical between the groups. Our data show that the fundamentals of prion propagation and pathological manifestation are not influenced by the oxidative DNA damage repair mechanisms studied here, but that progressive accumulation of oxidative lesions may accelerate the final toxic phase of prion disease.

Original languageEnglish
Pages (from-to)1-7
Number of pages7
JournalFree Radical Biology and Medicine
Volume68
DOIs
Publication statusPublished - Jan 1 2014

Fingerprint

Prion Diseases
Prions
DNA Damage
Repair
DNA Repair
DNA
Scrapie
Poisons
Adenine
Knockout Mice
Reactive Oxygen Species
Peptide Hydrolases
Western Blotting
Pathology
Oxidation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

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Accelerated clinical course of prion disease in mice compromised in repair of oxidative DNA damage. / Jalland, Clara M.O.; Benestad, Sylvie L.; Ersdal, Cecilie; Scheffler, Katja; Suganthan, Rajikala; Nakabeppu, Yusaku; Eide, Lars; Bjørås, Magnar; Tranulis, Michael A.

In: Free Radical Biology and Medicine, Vol. 68, 01.01.2014, p. 1-7.

Research output: Contribution to journalArticle

Jalland, CMO, Benestad, SL, Ersdal, C, Scheffler, K, Suganthan, R, Nakabeppu, Y, Eide, L, Bjørås, M & Tranulis, MA 2014, 'Accelerated clinical course of prion disease in mice compromised in repair of oxidative DNA damage', Free Radical Biology and Medicine, vol. 68, pp. 1-7. https://doi.org/10.1016/j.freeradbiomed.2013.11.013
Jalland, Clara M.O. ; Benestad, Sylvie L. ; Ersdal, Cecilie ; Scheffler, Katja ; Suganthan, Rajikala ; Nakabeppu, Yusaku ; Eide, Lars ; Bjørås, Magnar ; Tranulis, Michael A. / Accelerated clinical course of prion disease in mice compromised in repair of oxidative DNA damage. In: Free Radical Biology and Medicine. 2014 ; Vol. 68. pp. 1-7.
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