Fusion of Doppel to Octapeptide Repeat and N‐Terminal Half of Hydrophobic Region of Prion Protein Confers Resistance to Serum Deprivation

Abstract

Our previous studies have shown an essential role played by the octapeptide repeat region (OR) and the N‐terminal half of hydrophobic region (HR) in the anti‐apoptotic activity of prion protein (PrP). As PrP‐like protein Doppel (Dpl), which structurally resembles an N‐terminally truncated PrP, did not show any anti‐apoptotic activity, we examined apoptosis of HpL3–4 cells expressing Dpl fused to various lengths of the N‐terminal region of PrP to investigate whether the PrP/Dpl fusion proteins retain anti‐apoptotic function. HpL3–4 cells expressing Dpl fused to PrP(1–124) with the OR and N‐terminal half of HR of PrP showed anti‐apoptotic function, whereas Dpl fused to PrP(1–95) with OR did not rescue cells from apoptotic cell death induced by serum deprivation. These results indicate that the OR and N‐terminal half of HR of PrP retains anti‐apoptotic activity similar to full‐length PrP.

Neurotoxic Prion Protein (PrP) Fragment 106-126 Requires the N-terminal Half of the Hydrophobic Region of PrP in the PrP-Deficient Neuronal Cell Line

“…In summary, PrP C indicated in cells an anti-apoptotic function [23][24][25][39][40][41] mediated by upregulation of cellular SOD, while STI1 is involved in PrP C -dependent SOD activation [40]. This enzymatic activation may have been abrogated by aged peptide PrP(106-126), probably as a result of inhibition of the interaction between PrP C and STI1 [42].…”

BCL‐2 counteracts Doppel‐induced apoptosis of prion‐protein‐deficient Purkinje cells in the Ngsk Prnp0/0 mouse

“…Interestingly, an important function of BCL-2 is to antagonize the pro-apoptotic effect of BAX through direct interaction at this BH2 domain (Oltvai et al, 1993;Gross et al, 1999;Cheng et al, 2001), which is missing in both Dpl and mutated neurotoxic forms of PrP: DPrP (Shmerling et al, 1998;Flechsig et al, 2003;Li et al, 2007) and Tg(PG14)PrP (Chiesa et al, 1998). Indeed, fusion of Dpl to a BH2-containing octapeptide repeat and the N-terminal half of hydrophobic region of PrP c confer resistance to serum deprivation (Lee et al, 2006). Interestingly, N-terminally deleted forms of PrP c have been recently shown to activate both Bax-dependent and Bax-independent apoptotic pathways (Li et al, 2007).…”

Prion Stability and Infectivity in the Environment

“…The GPI linkage also does not appear to have a role in formation of the infections prion [34], although the GPI-linked PrP C is necessary for disease progression [35]. In addition to a growing list of possible functions in normal neurons, PrP expression has also been shown to confer anti-apoptotic activity in cultured neuronal cells [36,37].…”