Lethal recessive myelin toxicity of prion protein lacking its central domain

Abstract

PrP C -deficient mice expressing prion protein variants with large amino-proximal deletions (termed PrP DF ) suffer from neurodegeneration, which is rescued by full-length PrP C . We now report that expression of PrP DCD , a PrP variant lacking 40 central residues (94-134), induces a rapidly progressive, lethal phenotype with extensive central and peripheral myelin degeneration. This phenotype was rescued dose-dependently by coexpression of full-length PrP C or PrP C lacking all octarepeats. Expression of a PrP C variant lacking eight residues (114-121) was innocuous in the presence or absence of full-length PrP C , yet enhanced the toxicity of PrP DCD and diminished that of PrP DF . Therefore, deletion of the entire central domain generates a strong recessive-negative mutant of PrP C , whereas removal of residues 114-121 creates a partial agonist with context-dependent action. These findings suggest that myelin integrity is maintained by a constitutively active neurotrophic protein complex involving PrP C , whose effector domain encompasses residues 94-134.

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

“…A) Scheme proposed by Baumann and coworkers which suggests that PrP CD interaction with a putative PrP c receptor could trigger neuronal degeneration. This interaction could play as a stabilized dominant negative (adapted from Baumann et al, 2007). B) Model suggested by Li and coworkers for PrP CR form.…”

“…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.…”

“…These three "PrP c -like" proteins appear to trigger the same death pathways; the histological characteristics of the degenerating cerebellum in these mice are similar (regarding CGN/PC death, white matter vacuolization), as are their biochemical properties (membrane attachment and vesicular trafficking). A copy of Prnp rescues these neurodegenerative processes, thereby pointing to a common ligand-mediated toxicity mechanism rather than a misfolding protein (Baumann et al, 2007;Li et al, 2007b;Shmerling et al, 1998).…”

“…This model has recently been completed with the generation of PrP c knockout mice overexpressing a PrP c isoform that lacks the CD (residues 94-134), the PrP CD line. These mice present an exacerbated lethal ataxic syndrome, which is counteracted by the introduction of the complete PrP c or PrP c protein devoid of the OR region (Baumann et al, 2007). PrP CD mice constitute a stabilized dominant negative, and the OR region stabilizes PrP c -PrP c receptor interaction, but does not contribute directly to signaling (Baumann et al, 2007) (see Fig.…”

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].…”