Title:
Mouse models of DNA repair and neurological disease
-Insight from neuropathology of DNA repair-deficiency disorders-

Hironobu Nakane, MD., Ph.D.
Assistant Professor
Division of Genome Morphology, Department of Functional, Morphological and Regulatory Science, Faculty of Medicine, Tottori University , Japan

Abstract:
The ATM (ataxia telangiectasia, mutated) and MRN complex (Mre11/RAD50/NBS1) are essential for the cellular response to DNA double-strand break s. ATM defect causes ataxia telangiectasia (A-T), while MRN malfunction can lead to A-T-like disease (ATLD) or Nijmegen breakage syndrome (NBS). Neuropathology is a hallmark of these diseases, whereby neurodegeneration occurs in A-T and ATLD while microcephaly characterizes NBS. To understand the contrasting neuropathology resulting from Mre11 or Nbs1 hypomorphic mutations, we analyzed neural tissue from Mre11 ^ATLD1/ATLD1 and Nbs1 ^ΔB/ΔB mice after genotoxic insult. We found an apparent resistance to DNA damage-induced apoptosis after ionizing radiation or DNA ligase IV ( Lig4 ) loss in the Mre11 ^ATLD1/ATLD1 nervous system that was associated with defective Atm activation and phosphorylation of its substrates Chk2 and p53. Oppositely, DNA damage-induced Atm phosphorylation was defective in Nbs1 ^ΔB/ΔB neural tissue, although apoptosis occurred normally. We also conditionally disrupted Lig4 throughout the nervous system using Nestin-cre (Lig4 ^Nes-Cre ), and while viable, these mice showed remarkable microcephaly and a prominent age-dependent accumulation of DNA damage throughout the brain. Either Atm ^-/- or Mre11^ATLD1/ATLD1 genetic backgrounds, but not Nbs1 ^ΔB/ΔB , rescued Lig4 ^Nes-Cre microcephaly. Thus, DNA damage signaling in the nervous system is different between ATLD and NBS and probably explains their respective neuropathology .
Rare xeroderma pigmentosum group G (XP-G) patients with features of Cockayne syndrome(CS), the so-called XP-CS, exhibit skin abnormalities, growth failure, life-shortening and neurological dysfunctions . CS is also a devastating premature aging disease. XPG is a structure-specific DNA endonuclease that functions in nucleotide excision repair ( NER) and forms a stable protein complex with TFIIH in the regulation of gene expression. The Xpg null mice exhibited severe growth defect, neurological abnormalities including ataxia, life-shortening. We examined pathological changes corresponding to clinical symptomes in the Xpg null mice, such as emaciation, ataxia, joint contractures. Xpg null mice provide a good animal model for studying the unknown mechanisms underlying clinical symptoms of XP-G/CS, CS in humans. This data may help to improve the QOL of CS patients.
Accordingly, understanding the DNA damage response mechanism in the nervous system through the use of mouse models is very important for finding new treatments for neurodegeneration.

References:
1) Shull ER, Lee Y, Nakane H, Stracker TH, Zhao J, Russell HR, Petrini JH, McKinnon PJ. Differential DNA damage signaling accounts for distinct neural apoptotic responses in ATLD and NBS. Genes Dev. 2009;23:171-80.

2) Harada YN, Shiomi N, Koike M, Ikawa M, Okabe M, Hirota S, Kitamura Y,Kitagawa M, Matsunaga T, Nikaido O, Shiomi T. Postnatal growth failure, short lifespan, and early onset of cellular senescence and subsequent immortalization in micelacking the xeroderma pigmentosum group G gene. Mol. Cell. Biol. 1999;19:2366-2372