title: Mitochondrial localization of cellular prion protein (PrPC) invokes neuronal apoptosis in aged transgenic mice overexpressing PrPC.
abstract: Recent studies suggest that the disease isoform of prion protein (PrPSc) is non-neurotoxic in the absence of cellular isoform of prion protein (PrPC), indicating that PrPC may participate directly in the neurodegenerative damage by itself. Meanwhile, transgenic mice harboring a high-copy-number of wild-type mouse (Mo) PrPC develop a spontaneous neurological dysfunction in an age-dependent manner, even without inoculation of PrPSc and thus, investigations of these aged transgenic mice may lead to the understanding how PrPC participate in the neurotoxic property of PrP. Here we demonstrate mitochondria-mediated neuronal apoptosis in aged transgenic mice overexpressing wild-type MoPrPC (Tg(MoPrP)4053/FVB). The aged mice exhibited an aberrant mitochondrial localization of PrPC 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 PrPC-related, mitochondria-mediated apoptosis. Hence, the neurotoxic property of PrPC could be explained by the mitochondria-mediated neuronal apoptosis, at least in part.
authors.affiliation: Department of a Cortical Function Disorders, National Institute of Neuroscience (NIN), National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo 187-8502, Japan.
authors.forename: Naomi S
authors.initials: NS
authors.lastname: Hachiya
authors.forename: Makiko
authors.initials: M
authors.lastname: Yamada
authors.forename: Kota
authors.initials: K
authors.lastname: Watanabe
authors.forename: Akiko
authors.initials: A
authors.lastname: Jozuka
authors.forename: Takuya
authors.initials: T
authors.lastname: Ohkubo
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sano
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Kozuka
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sakasegawa
authors.forename: Kiyotoshi
authors.initials: K
authors.lastname: Kaneko
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western / Q000379:methods; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002918:Chymotrypsin / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005978:Glutathione / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron / Q000379:methods; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D018832:Molecular Chaperones / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013367:Submitochondrial Particles / Q000378:metabolism / Q000648:ultrastructure; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D011328:Prions; D020033:Protein Isoforms; D045304:Cytochromes c; D013482:Superoxide Dismutase; D002918:Chymotrypsin; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione