Cell-autonomous PrP-Doppel interaction regulates apoptosis in PrP gene-deficient neuronal cells.
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.
Sakudo
Akikazu
A
Department of Molecular Immunology, School of Agricultural and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
Lee
Deug-chan
DC
Nakamura
Izuru
I
Taniuchi
Yojiro
Y
Saeki
Keiichi
K
Matsumoto
Yoshitsugu
Y
Itohara
Shigeyoshi
S
Ikuta
Kazuyoshi
K
Onodera
Takashi
T
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
D000682:Amyloid; D058851:GPI-Linked Proteins; D000072002:Prion Proteins; D011328:Prions; C122036:Prnd protein, mouse; C512657:Prnp protein, mouse; D011498:Protein Precursors