title: Cell-autonomous PrP-Doppel interaction regulates apoptosis in PrP gene-deficient neuronal cells.
abstract: The Prnd-encoded prion protein (PrP)-like protein, Doppel (Dpl), is a homologue of Prnp-encoded PrP, and is N-glycosylated protein with glycosylphosphatidylinositol anchor like PrP. Recently, ectopic expressions of Prnp/Prnd chimeric mRNAs have been identified as the cause of late-onset ataxia observed in several lines of Prnp-knockout mice such as ZrchII, Ngsk, Rcm0, and Rikn mice. However, it remains unclear whether the toxic effect of Dpl expression is a cell-autonomous mechanism but rather reflect a systemic process of heterogeneous cell population in the brain. In this study, the cell-autonomous role of Dpl was estimated by investigating PrP-deficient cells (HpL3-4)-the SV40 large T-antigen immortalized and Rikn Prnp(-/-) mice-derived neuronal cell line expressing Prnp/Prnd chimeric mRNAs. The reverse transcription polymerase chain reaction revealed that serum deprivation did not increase Prnp/Prnd chimeric mRNAs, which in fact was translated into a small amount of Dpl in HpL3-4 cells, whereas serum deprivation induced apoptotic cell death of HpL3-4 cells. Dpl overexpression enhanced apoptotic cell death, whereas the toxic effect of Dpl on apoptotic cell death was neutralized by PrP expression. These results indicate that Dpl elicited dose-dependently toxic effects on PrP-deficient cells without affecting on PrP-expressing cells, suggesting that the PrP-Dpl interaction can regulate cell death in a cell-autonomous manner.
authors.affiliation: Department of Molecular Immunology, School of Agricultural and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Akikazu
authors.initials: A
authors.lastname: Sakudo
authors.forename: Deug-chan
authors.initials: DC
authors.lastname: Lee
authors.forename: Izuru
authors.initials: I
authors.lastname: Nakamura
authors.forename: Yojiro
authors.initials: Y
authors.lastname: Taniuchi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Saeki
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Itohara
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Ikuta
authors.forename: Takashi
authors.initials: T
authors.lastname: Onodera
mesh_terms: D000682:Amyloid / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D058851:GPI-Linked Proteins; D020868:Gene Silencing; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D000072002:Prion Proteins; D011328:Prions / Q000378:metabolism*; D011498:Protein Precursors / Q000172:deficiency* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000682:Amyloid; D058851:GPI-Linked Proteins; D000072002:Prion Proteins; D011328:Prions; C122036:Prnd protein, mouse; C512657:Prnp protein, mouse; D011498:Protein Precursors