Accumulation of DNA damage and reduced levels of nicotine adenine dinucleotide in the brains of Atm-deficient mice.
Ataxia-telangiectasia (A-T) is a human genetic disorder caused by mutational inactivation of the ATM gene. A-T patients display a pleiotropic phenotype, in which a major neurological feature is progressive ataxia due to degeneration of cerebellar Purkinje and granule neurons. Disruption of the mouse Atm locus creates a murine model of A-T that exhibits most of the clinical and cellular features of the human disease, but the neurological phenotype is barely expressed. We present evidence for the accumulation of DNA strand breaks in the brains of Atm(-/-), supporting the notion that ATM plays a major role in maintaining genomic stability. We also show a perturbation of the steady state levels of pyridine nucleotides. There is a significant decrease in both the reduced and the oxidized forms of NAD and in the total levels of NADP(T) and NADP(+) in the brains of Atm(-/-) mice. The changes in NAD(T), NADH, NAD(+), NADP(T), and NADP(+) were progressive and observed primarily in the cerebellum of 4-month-old Atm(-/-) mice. Higher rates of mitochondrial respiration were also recorded in 4-month-old Atm(-/-) cerebella. Taken together, our findings support the hypothesis that absence of functional ATM results in continuous stress, which may be an important cause of the degeneration of cerebellar neurons in A-T.
Stern
Nora
N
Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Hochman
Ayala
A
Zemach
Naty
N
Weizman
Nir
N
Hammel
Ilan
I
Shiloh
Yosef
Y
Rotman
Galit
G
Barzilai
Ari
A
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D001921:Brain / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002531:Cerebellum / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins; D020287:In Situ Nick-End Labeling; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D009249:NADP / Q000032:analysis; D010101:Oxygen Consumption; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D009243:NAD; D000246:Adenosine Diphosphate Ribose; D009249:NADP; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases