Association of endothelial nitric oxide synthase and mitochondrial dysfunction in the hippocampus of scrapie-infected mice.
The elevation of nitric oxide (NO) within the central nervous system (CNS) is known to be associated with the pathogenesis of neurodegenerative diseases such as HIV-associated dementia (HAD), brain ischemia, Parkinson's disease, and Alzheimer's disease. NO is enzymatically formed by the enzyme nitric oxide synthase (NOS). There are two forms of NOS, the constitutive and the inducible form. The constitutive form is present in endothelial cells (eNOS) and neurons (nNOS). The inducible form (iNOS) is expressed in various cell types including astroglia and microglia of the CNS. Using an animal model, we investigated the involvement of eNOS in the pathology of prion disease. We showed dramatic upregulation of eNOS immunoreactivity in reactive astroglial cells in the hippocampus in the prion disease animal model, scrapie in mice. Expression of eNOS was upregulated in cytosolic and mitochondrial fractions of whole brain. In the hippocampal region, eNOS was widely overexpressed in various components of the cell. We found that eNOS dramatically accumulated in hippocampal mitochondria and was particularly prevalent in structurally dysfunctional mitochondria. In association with the accumulation of eNOS in mitochondria, we showed that mitochondrial superoxide dismutase (Mn-SOD or SOD2), cytochrome c, and ATP activity were downregulated both in whole brain and in the hippocampal region. These results indicate that eNOS plays a role in the development of dysfunctional mitochondria and this, in turn, could induce some of the histopathological changes seen in prion diseases.
Park
Jeong-Ho
JH
Ilsong Institute of Life Science, Hallym University, Gwanyang-dong Dongan-gu, Anyang, Gyeonggi-do, Republic of Korea.
Kim
Boe-Hyun
BH
Park
Seok-Joo
SJ
Jin
Jae-Kwang
JK
Jeon
Yong-Chul
YC
Wen
Guang Y
GY
Shin
Hae-Young
HY
Carp
Richard I
RI
Kim
Yong-Sun
YS
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000473:pathology; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D012608:Scrapie / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D000255:Adenosine Triphosphate; D045304:Cytochromes c; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase