TY - JOUR
T1 - Mitochondrial localization of cellular prion protein (PrP C) invokes neuronal apoptosis in aged transgenic mice overexpressing PrP C
AU - Hachiya, Naomi S.
AU - Yamada, Makiko
AU - Watanabe, Kota
AU - Jozuka, Akiko
AU - Ohkubo, Takuya
AU - Sano, Kenichi
AU - Takeuchi, Yoshio
AU - Kozuka, Yoshimichi
AU - Sakasegawa, Yuji
AU - Kaneko, Kiyotoshi
N1 - Funding Information:
We thank S.B. Prusiner for providing Tg(MoPrP)4053/FVB, T. Onodera for providing HpL3-4 cells, E. Nannri, K. Ishibashi, C. Ota, Y. Yamaura, and S. Wajima for technical assistance. We are indebted to G. Schatz, T. Omura, K. Mihara, R. Scheckman, and T. Momoi for helpful comments. This work was supported by grants from the Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Agency, Health and Labour Sciences Research Grants, Research on Advanced Medical Technology, nano-001, and the Ministry of Health, Labor and Welfare of Japan.
PY - 2005/2/10
Y1 - 2005/2/10
N2 - Recent studies suggest that the disease isoform of prion protein (PrP Sc) is non-neurotoxic in the absence of cellular isoform of prion protein (PrP C), indicating that PrP C may participate directly in the neurodegenerative damage by itself. Meanwhile, transgenic mice harboring a high-copy-number of wild-type mouse (Mo) PrP C develop a spontaneous neurological dysfunction in an age-dependent manner, even without inoculation of PrP Sc and thus, investigations of these aged transgenic mice may lead to the understanding how PrP C participate in the neurotoxic property of PrP. Here we demonstrate mitochondria-mediated neuronal apoptosis in aged transgenic mice overexpressing wild-type MoPrP C (Tg(MoPrP)4053/FVB). The aged mice exhibited an aberrant mitochondrial localization of PrP C concomitant with decreased proteasomal activity, while younger littermates did not. Such aberrant mitochondrial localization was accompanied by decreased mitochondrial manganese superoxide dismutase (Mn-SOD) activity, cytochrome c release into the cytosol, caspase-3 activation, and DNA fragmentation, most predominantly in hippocampal neuronal cells. Following cell culture studies confirmed that decrease in the proteasomal activity is fundamental for the PrP C-related, mitochondria-mediated apoptosis. Hence, the neurotoxic property of PrP C could be explained by the mitochondria-mediated neuronal apoptosis, at least in part.
AB - Recent studies suggest that the disease isoform of prion protein (PrP Sc) is non-neurotoxic in the absence of cellular isoform of prion protein (PrP C), indicating that PrP C may participate directly in the neurodegenerative damage by itself. Meanwhile, transgenic mice harboring a high-copy-number of wild-type mouse (Mo) PrP C develop a spontaneous neurological dysfunction in an age-dependent manner, even without inoculation of PrP Sc and thus, investigations of these aged transgenic mice may lead to the understanding how PrP C participate in the neurotoxic property of PrP. Here we demonstrate mitochondria-mediated neuronal apoptosis in aged transgenic mice overexpressing wild-type MoPrP C (Tg(MoPrP)4053/FVB). The aged mice exhibited an aberrant mitochondrial localization of PrP C concomitant with decreased proteasomal activity, while younger littermates did not. Such aberrant mitochondrial localization was accompanied by decreased mitochondrial manganese superoxide dismutase (Mn-SOD) activity, cytochrome c release into the cytosol, caspase-3 activation, and DNA fragmentation, most predominantly in hippocampal neuronal cells. Following cell culture studies confirmed that decrease in the proteasomal activity is fundamental for the PrP C-related, mitochondria-mediated apoptosis. Hence, the neurotoxic property of PrP C could be explained by the mitochondria-mediated neuronal apoptosis, at least in part.
KW - Mitochondria-mediated apoptosis
KW - Mitochondrial localization
KW - PrP
KW - Proteasomal activity
KW - Superoxide dismutase activity
UR - http://www.scopus.com/inward/record.url?scp=19944428175&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=19944428175&partnerID=8YFLogxK
U2 - 10.1016/j.neulet.2004.10.044
DO - 10.1016/j.neulet.2004.10.044
M3 - Article
C2 - 15644272
AN - SCOPUS:19944428175
VL - 374
SP - 98
EP - 103
JO - Neuroscience Letters
JF - Neuroscience Letters
SN - 0304-3940
IS - 2
ER -