Neonatal lethality in transgenic mice expressing prion protein with a deletion of residues 105–125

Abstract

To identify sequence domains important for the neurotoxic and neuroprotective activities of the prion protein (PrP), we have engineered transgenic mice that express a form of murine PrP deleted for a conserved block of 21 amino acids (residues 105-125) in the unstructured, N-terminal tail of the protein. These mice spontaneously developed a severe neurodegenerative illness that was lethal within 1 week of birth in the absence of endogenous PrP. This phenotype was reversed in a dose-dependent fashion by coexpression of wild-type PrP, with five-fold overexpression delaying death beyond 1 year. The phenotype of Tg(PrPD105-125) mice is reminiscent of, but much more severe than, those described in mice that express PrP harboring larger deletions of the N-terminus, and in mice that ectopically express Doppel, a PrP paralog, in the CNS. The dramatically increased toxicity of PrPD105-125 is most consistent with a model in which this protein has greatly enhanced affinity for a hypothetical receptor that serves to transduce the toxic signal. We speculate that altered binding interactions involving the 105-125 region of PrP may also play a role in generating neurotoxic signals during prion infection.

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

“…As expected, in comparison with Dpl mice, in N-terminal truncated mice, the neocortex as well as other brain regions were preserved, but the cerebellum was strongly affected and cerebellar neurons showed degeneration (Li et al, 2007b;Shmerling et al, 1998).…”

“…2). In this respect, it is well khown that PrP c bind amyloid fibrils (see (Li et al, 2007b) for comments).…”

“…However, it has been proposed that myelin pathology induced by N-terminally truncated PrP c acts through independent mechanisms, in contrast to CGN depletion (Radovanovic et al, 2005). Recent studies have shown that overexpression of PrP c devoid of CD or a fragment of CD (residues 105-125) in PrP c knockout mice promotes an exacerbated ataxic syndrome, causing lethality at approximately postnatal day 20 (Baumann et al, 2007;Li et al, 2007b). More in-depth studies using these knockout mice would be useful to elucidate the physiological functions of the domains of PrP c , and also to improve our understanding of the putative signaling pathways involved in prion-related pathologies.…”

Five Questions on Prion Diseases

“…This suggests that truncated PrP C competes with PrP C -like molecules through a shared receptor [20], [21]. Transgenic mice expressing deletion extended to the very end of N-terminus of PrP C (Δ23–134) are healthy, suggesting that residues 23–31 are involved in Shmerling's and Baumann's disease [22].…”

Rodent models for prion diseases

“…-mapping PrP regions involved in or required for PrP conversion and prion replication [36,37,44,56,57,63,78,80]; -studies on the physiological role of PrP C and the contributions of individual molecular regions to these functions [65]; -studies on molecular aspects of species barrier effects by mutation of single or limited numbers of positions within the PrP [20,41,51,76,77,82]; -modelling of familial forms of human prion diseases [3,4,60]; -analysis of the cell specificity of prion propagation [48,71,72]; -analysis of the role of PrP glycosylation [22,64]; -studies on the mechanisms of prion spread [11,12]; -studies on the neuropathological roles of PrP C and of PrP D in prion disease [39]; -studies on the function of PrP Doppel [34].…”