Transgene-driven expression of the Doppel protein in Purkinje cells causes Purkinje cell degeneration and motor impairment

Abstract

The Doppel (Dpl) and Prion (PrP) proteins show 25% sequence identity and share several structural features with only minor differences. Dpl shows a PrP-like fold of its C-terminal globular domain and lacks the flexible N-terminal tail. The physiological functions of both proteins are unknown. However, ubiquitous Dpl overexpression in the brain of PrP knockout mice correlated with ataxia and Purkinje cell degeneration in the cerebellum. Interestingly, a similar phenotype was reported in transgenic mice expressing an N-terminally truncated PrP (⌬PrP) in Purkinje cells by the L7 promoter (TgL7-⌬PrP). Coexpression of full-length PrP rescued both the neurological syndromes caused by either Dpl or ⌬PrP. To evaluate whether the two proteins caused cerebellar neurodegeneration by the same mechanism, we generated transgenic mice selectively expressing Dpl in Purkinje cells by the same L7 promoter. Such mice showed ataxia and Purkinje cell loss that depended on the level of Dpl expression. Interestingly, the effects of high levels of Dpl were not counterbalanced by the presence of two Prnp alleles. By contrast, PrP coexpression was sufficient to abrogate motor impairment and to delay the neurodegenerative process caused by moderate level of Dpl. A similar situation was reported for the corresponding TgL7-⌬PrP mice supporting the concept that Dpl and ⌬PrP cause cell death, possibly by interfering with a common signaling cascade essential for cell survival.

Dominant-negative Effects of the N-terminal Half of Prion Protein on Neurotoxicity of Prion Protein-like Protein/Doppel in Mice

“…However, others, such as Zrch I and Npu, neither ectopically expressed Dpl nor exhibited ataxia and Purkinje cell degeneration (4,5). It was finally confirmed that Dpl is neurotoxic, and PrP C antagonizes the neurotoxicity of Dpl by a demonstration that transgenically expressed Dpl caused ataxia and Purkinje cell degeneration in nonataxic Zrch I Prnp 0/0 mice but not in wild-type mice (7)(8)(9). However, the exact mechanism of the antagonistic interaction of PrP C and Dpl remains unknown.…”

“…In contrast, Dpl, the first identified structural homologue of the C-terminal domain of PrP C , is neurotoxic causing ataxia and Purkinje cell degeneration in mice (7)(8)(9). Interestingly, PrP C functionally antagonizes the neurotoxicity of Dpl, preventing the neurode- generation (7)(8)(9). However, the mechanism of the antagonistic interaction between PrP C and Dpl or the truncated PrPs remains to be elucidated.…”

“…For instance, Prnp 0/0 mice are highly sensitive to ischemic or traumatic brain damage, developing more severe pathological changes than in wild-type mice (24 -27). In contrast, Dpl, the first identified structural homologue of the C-terminal domain of PrP C , is neurotoxic causing ataxia and Purkinje cell degeneration in mice (7)(8)(9). Interestingly, PrP C functionally antagonizes the neurotoxicity of Dpl, preventing the neurode- generation (7)(8)(9).…”

Genetic Mapping of Activity Determinants within Cellular Prion Proteins

“…PrP C Expression Blocks Dpl-induced Toxicity-A key criterion to assess the accuracy of the in vitro model described above is the protective effect of PrP C expression, as this has been documented in all transgenic paradigms examined to date (20,22,41,42). Because cerebellar cells overexpressing hamster PrP C derived from Tg(SHaPrP)7 mice (35) were resistant to the toxic effect of Dpl (not shown), as in Tg mice (20,43), we investigated whether this was also the case for PrP C expressed at endogenous levels.…”

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

“…PCs present no signs of degeneration because of enhancer-mediated splicing that prevents F35 expression in these neurons (Shmerling et al, 1998). However, targeted-PC expression of the F35 construct by a specific promoter induces PC death and ataxia (Anderson et al, 2004;Flechsig et al, 2003). Similarly to Dpl-mediated degeneration, Shmerling syndrome is rescued by reintroducing the full-length Prnp (Shmerling et al, 1998).…”