Up-regulation of hMUTYH, a DNA repair enzyme, in the mitochondria of substantia nigra in Parkinson's disease.
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 alpha4. 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.
Arai
Takeo
T
Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan.
Fukae
Jiro
J
Hatano
Taku
T
Kubo
Shin-ichiro
S
Ohtsubo
Toshio
T
Nakabeppu
Yusaku
Y
Mori
Hideo
H
Mizuno
Yoshikuni
Y
Hattori
Nobutaka
N
D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D004247:DNA / Q000235:genetics; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D010300:Parkinson Disease / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000201:enzymology* / Q000473:pathology; D015854:Up-Regulation / Q000502:physiology*
D015415:Biomarkers; D012333:RNA, Messenger; D004247:DNA; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D045643:DNA Repair Enzymes