Mitochondrial localization of cellular prion protein (PrP C) invokes neuronal apoptosis in aged transgenic mice overexpressing PrP C

Naomi S. Hachiya, Makiko Yamada, Kota Watanabe, Akiko Jozuka, Takuya Ohkubo, Kenichi Sano, Yoshio Takeuchi, Yoshimichi Kozuka, Yuji Sakasegawa, Kiyotoshi Kaneko

研究成果: Article査読

29 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)98-103
ページ数6
ジャーナルNeuroscience Letters
374
2
DOI
出版ステータスPublished - 2005 2 10

ASJC Scopus subject areas

  • 神経科学(全般)

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