Increased oxidative damage to DNA in a transgenic mouse model of Huntington's disease

Mitochondrial dysfunction and oxidative damage may play a role in the pathogenesis of Huntington's disease (HD). We examined concentrations of 8‐hydroxy‐2‐deoxyguanosine (OH8dG), a well‐established marker of oxidative damage to DNA, in a transgenic mouse model of HD (R6/2). Increased concentrations of OH8dG were found in the urine, plasma and striatal microdialysates of the HD mice. Increased concentrations were also observed in isolated brain DNA at 12 and 14 weeks of age. Immunocytochemistry showed increased OH8dG staining in late stages of the illness. These results suggest that oxidative damage may play a role in the pathogenesis of neuronal degeneration in the R6/2 transgenic mouse model of HD.

[1]  M. Beal,et al.  Increased oxidative damage to DNA in ALS patients. , 2000, Free radical biology & medicine.

[2]  L. Loeb,et al.  8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G----T and A----C substitutions. , 1992, The Journal of biological chemistry.

[3]  Huda Y. Zoghbi,et al.  Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1 , 2000, Nature Neuroscience.

[4]  Patrizia Mecocci,et al.  Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease , 1994, Annals of neurology.

[5]  Liping Li,et al.  The roles of free radicals in amyotrophic lateral sclerosis: reactive oxygen species and elevated oxidation of protein, DNA, and membrane phospholipids , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  B. Halliwell,et al.  Damage to the DNA bases in mammalian chromatin by hydrogen peroxide in the presence of ferric and cupric ions. , 1991, Archives of biochemistry and biophysics.

[7]  George Perry,et al.  RNA Oxidation Is a Prominent Feature of Vulnerable Neurons in Alzheimer’s Disease , 1999, The Journal of Neuroscience.

[8]  S. W. Davies,et al.  Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human huntington disease gene. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[9]  G. Reynolds,et al.  Distribution of phosphate-activated glutaminase, succinic dehydrogenase, pyruvate dehydrogenase and γ-glutamyl transpeptidase in post-mortem brain from Huntington's disease and agonal cases , 1985, Journal of the Neurological Sciences.

[10]  C. Portera-Cailliau,et al.  Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[11]  P. Mecocci,et al.  Oxidative damage to mitochondrial DNA in Huntington's disease parietal cortex , 1999, Neuroscience Letters.

[12]  S. Toyokuni,et al.  Intranuclear Distribution of 8-hydroxy-2'-deoxyguanosine: An Immunocytochemical Study , 1999, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[13]  S. Kawanishi,et al.  Oxidative DNA damage induced by simultaneous generation of nitric oxide and superoxide , 1995, FEBS letters.

[14]  B. Halliwell,et al.  No Evidence for Increased Oxidative Damage to Lipids, Proteins, or DNA in Huntington's Disease , 2000, Journal of neurochemistry.

[15]  S. W. Davies,et al.  Exon 1 of the HD Gene with an Expanded CAG Repeat Is Sufficient to Cause a Progressive Neurological Phenotype in Transgenic Mice , 1996, Cell.

[16]  C. Ríos,et al.  Striatal oxidative damage parallels the expression of a neurological phenotype in mice transgenic for the mutation of Huntington’s disease , 2000, Brain Research.

[17]  Robert H. Brown,et al.  Evidence of Increased Oxidative Damage in Both Sporadic and Familial Amyotrophic Lateral Sclerosis , 1997, Journal of neurochemistry.

[18]  A H Schapira,et al.  Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse , 2000, Annals of neurology.

[19]  M. Beal,et al.  A carbon column-based liquid chromatography electrochemical approach to routine 8-hydroxy-2'-deoxyguanosine measurements in urine and other biologic matrices: a one-year evaluation of methods. , 1999, Free radical biology & medicine.

[20]  M. Sheng,et al.  Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization , 2000, Nature Neuroscience.

[21]  M. Beal,et al.  Oxidative damage and metabolic dysfunction in Huntington's disease: Selective vulnerability of the basal ganglia , 1997, Annals of neurology.