Expression of Amino-Terminally Truncated PrP in the Mouse Leading to Ataxia and Specific Cerebellar Lesions

Abstract

The physiological role of prion protein (PrP) remains unknown. Mice devoid of PrP develop normally but are resistant to scrapie; introduction of a PrP transgene restores susceptibility to the disease. To identify the regions of PrP necessary for this activity, we prepared PrP knockout mice expressing PrPs with amino-proximal deletions. Surprisingly, PrP lacking residues 32-121 or 32-134, but not with shorter deletions, caused severe ataxia and neuronal death limited to the granular layer of the cerebellum as early as 1-3 months after birth. The defect was completely abolished by introducing one copy of a wild-type PrP gene. We speculate that these truncated PrPs may be nonfunctional and compete with some other molecule with a PrP-like function for a common ligand.

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).…”

“…Prnp knockout mice overexpressing the C-terminal portion of PrP c (lacking OR and CD) of the N-terminal domain (F35 mice) display CGN death, white matter pathology and a progressive and early lethal ataxic phenotype termed Shmerling syndrome (Radovanovic et al, 2005;Shmerling et al, 1998). PCs present no signs of degeneration because of enhancer-mediated splicing that prevents F35 expression in these neurons (Shmerling et al, 1998).…”

Production of cattle lacking prion protein

“…However, the phenotype in the synaptic function appears to be normal in other murine genetic backgrounds 33 .We have monitored sleep-wake activity in the knockout cattle, along with age-, sex-and breed-matched wild-type controls, at frequent intervals throughout the day and night for one week, but did not observe any obvious alterations. Some other Prnp −/− mouse models show subtle abnormalities, such as learning differences 34 , and deletion of parts of the murine Prnp ORF have more severe effects 35 , suggesting that complete ablation of PrP C function as done in this study may have less detrimental phenotypes than the partial manipulation or rearrangement of the Prnp ORF.…”

Five Questions on Prion Diseases

“…Interstitially deleted PrP C variants (Δ32–134; Δ94–134) elicit spontaneous neurodegeneration (Shmerling's and Baumann's disease), which is rescued by co-expression of full-length PrP C [19], [20]. This suggests that truncated PrP C competes with PrP C -like molecules through a shared receptor [20], [21].…”