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

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)98-103
Number of pages6
JournalNeuroscience Letters
Volume374
Issue number2
DOIs
Publication statusPublished - 2005 Feb 10

Keywords

  • Mitochondria-mediated apoptosis
  • Mitochondrial localization
  • PrP
  • Proteasomal activity
  • Superoxide dismutase activity

ASJC Scopus subject areas

  • Neuroscience(all)

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