Functionally Relevant Domains of the Prion Protein Identified In Vivo
Open Access
- 7 September 2009
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 4 (9), e6707
- https://doi.org/10.1371/journal.pone.0006707
Abstract
The prion consists essentially of PrPSc, a misfolded and aggregated conformer of the cellular protein PrPC. Whereas PrPC deficient mice are clinically healthy, expression of PrPC variants lacking its central domain (PrPΔCD), or of the PrP-related protein Dpl, induces lethal neurodegenerative syndromes which are repressed by full-length PrP. Here we tested the structural basis of these syndromes by grafting the amino terminus of PrPC (residues 1–134), or its central domain (residues 90–134), onto Dpl. Further, we constructed a soluble variant of the neurotoxic PrPΔCD mutant that lacks its glycosyl phosphatidyl inositol (GPI) membrane anchor. Each of these modifications abrogated the pathogenicity of Dpl and PrPΔCD in transgenic mice. The PrP-Dpl chimeric molecules, but not anchorless PrPΔCD, ameliorated the disease of mice expressing truncated PrP variants. We conclude that the amino proximal domain of PrP exerts a neurotrophic effect even when grafted onto a distantly related protein, and that GPI-linked membrane anchoring is necessary for both beneficial and deleterious effects of PrP and its variants.Keywords
This publication has 56 references indexed in Scilit:
- Prion Strain Discrimination Based on Rapid In Vivo Amplification and Analysis by the Cell Panel AssayPLOS ONE, 2009
- The POM Monoclonals: A Comprehensive Set of Antibodies to Non-Overlapping Prion Protein EpitopesPLOS ONE, 2008
- Scrapie-Induced Defects in Learning and Memory of Transgenic Mice Expressing Anchorless Prion Protein Are Associated with Alterations in the Gamma Aminobutyric Acid-Ergic PathwayJournal of Virology, 2008
- Dominant-negative Effects of the N-terminal Half of Prion Protein on Neurotoxicity of Prion Protein-like Protein/Doppel in MicePublished by Elsevier ,2008
- Motor behavioral and neuropathological deficits in mice deficient for normal prion protein expressionBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2007
- The Role of the Octarepeat Region in Neuroprotective Function of the Cellular Prion ProteinBrain Pathology, 2007
- Lethal recessive myelin toxicity of prion protein lacking its central domainThe EMBO Journal, 2007
- Neonatal lethality in transgenic mice expressing prion protein with a deletion of residues 105–125The EMBO Journal, 2007
- Prion-Induced Amyloid Heart Disease with High Blood Infectivity in Transgenic MiceScience, 2006
- Cellular Prion Protein and Caveolin‐1 Interaction in a Neuronal Cell Line Precedes Fyn/Erk 1/2 Signal TransductionBioMed Research International, 2006