NR ARPU
AU Hachiya,N.S.; Yamada,M.; Watanabe,K.; Jozuka,A.; Ohkubo,T.; Sano,K.; Takeuchi,Y.; Kozuka,Y.; Sakasegawa,Y.; Kaneko,K.
TI Mitochondrial localization of cellular prion protein (PrPc) invokes neuronal apoptosis in aged transgenic mice overexpressing PrPc
QU Neuroscience Letters 2005 Feb 10; 374(2): 98-103
PT journal article
AB 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.
MH Animals; Animals, Newborn; Apoptosis/*physiology; Blotting, Western/methods; Caspases/metabolism; Chymotrypsin/metabolism; Comparative Study; Cytochromes c/metabolism; Glutathione/metabolism; Heat-Shock Proteins/metabolism; Immunohistochemistry/methods; Membrane Glycoproteins/metabolism; Mice; Mice, Transgenic; Microscopy, Immunoelectron/methods; Mitochondria/*metabolism/ultrastructure; Molecular Chaperones/metabolism; Neurons/*cytology/metabolism; Prions/genetics/*metabolism; Protein Isoforms/genetics/metabolism; Protozoan Proteins/metabolism; Research Support, Non-U.S. Gov't; Submitochondrial Particles/metabolism/ultrastructure; Superoxide Dismutase/metabolism
AD Department of a Cortical Function Disorders, National Institute of Neuroscience (NIN), National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo 187-8502, Japan.
SP englisch
PO Irland