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Up-regulation of hMUTYH, a DNA repair enzyme, in the mitochondria of substantia nigra in Parkinson’s disease

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Abstract

There is ample evidence for the involvement of oxidative stress in mitochondrial DNA damage and repair mechanisms in Parkinson’s disease (PD). The human MutY homolog (hMUTYH) which removes misincorporated adenine opposite 8-oxoG in DNA functions in post-replication, and is localized in the nuclei and mitochondria. We hypothesized that hMUTYH is involved in the disease process of PD. To test our hypothesis, we performed immunohistochemical and biochemical studies on brains of patients with PD and those of control patients. Our results showed up-regulation of hMUTYH in the mitochondria of the SN of PD patients. Western blot analysis also revealed high hMUTYH levels in PD patients and expression of a 47-kDa molecule in the brains as the major isoform. This molecule was localized within the mitochondria as confirmed by double staining with a mitochondrial marker. To confirm the presence of this molecule, we examined the mRNAs of isoforms that translate to the 47-kDa molecule. Based on the amount of mRNAs, the major molecule was α4. Interestingly, this molecule lacks the mitochondria targeting sequence. Our results suggest that hMUTYH might be a useful marker of oxidative stress and that oxidative stress and genomic instability are important in the PD disease process.

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Author notes

  1. Yoshikuni Mizuno

    Present address: Research Institute for Disease of Old Ages, Juntendo University School of Medicine, Tokyo, Japan

Authors and Affiliations

  1. Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Takeo Arai, Jiro Fukae, Taku Hatano, Shin-ichiro Kubo, Hideo Mori, Yoshikuni Mizuno & Nobutaka Hattori

  2. Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan

    Toshio Ohtsubo & Yusaku Nakabeppu

Authors
  1. Takeo Arai
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  2. Jiro Fukae
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  3. Taku Hatano
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  4. Shin-ichiro Kubo
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  5. Toshio Ohtsubo
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  6. Yusaku Nakabeppu
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  7. Hideo Mori
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  8. Yoshikuni Mizuno
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  9. Nobutaka Hattori
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Correspondence to Nobutaka Hattori.

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Arai, T., Fukae, J., Hatano, T. et al. Up-regulation of hMUTYH, a DNA repair enzyme, in the mitochondria of substantia nigra in Parkinson’s disease. Acta Neuropathol 112, 139–145 (2006). https://doi.org/10.1007/s00401-006-0081-9

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  • DOI: https://doi.org/10.1007/s00401-006-0081-9

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