Ataxia with cerebellar lesions in mice expressing chimeric PrP-Dpl protein.
Mutations within the central region of prion protein (PrP) have been shown to be associated with severe neurotoxic activity similar to that observed with Dpl, a PrP-like protein. To further investigate this neurotoxic effect, we generated lines of transgenic (Tg) mice expressing three different chimeric PrP-Dpl proteins. Chi1 (amino acids 1-57 of Dpl replaced by amino acids 1-125 of PrP) and Chi2 (amino acids 1-66 of Dpl replaced by amino acids 1-134 of PrP) abrogated the pathogenicity of Dpl indicating that the presence of a N-terminal domain of PrP (23-134) reduced the toxicity of Dpl, as reported. However, when the amino acids 1-24 of Dpl were replaced by amino acids 1-124 of PrP, Chi3 Tg mice, which express the chimeric protein at a very low level, start developing ataxia at the age of 5-7 weeks. This phenotype was not counteracted by a single copy of full-length-PrP(c) but rather by its overexpression, indicating the strong toxicity of the chimeric protein Chi3. Chi3 Tg mice exhibit severe cerebellar atrophy with a significant loss of granule cells. We concluded that aa25 to aa57 of Dpl, which are not present in Chi1 and Chi2 constructs, confer toxicity to the protein. We tested this possibility by using the 25-57 Dpl peptide in primary culture of mouse embryo cortical neurons and found a significant neurotoxic effect. This finding identifies a protein domain that plays a role in mediating Dpl-related toxicity.
Laboratoire Adaptation et Pathogénie des Microorganismes, CNRS UMR 5163-UJF, 38042 Grenoble, France.
Catherine
C
Lemaire-Vieille
Yannick
Y
Bailly
Paul
P
Erlich
Corinne
C
Loeuillet
Jacques
J
Brocard
Anne-Marie
AM
Haeberlé
Guy
G
Bombarde
Camille
C
Rak
Valérie
V
Demais
Chantal
C
Dumestre-Pérard
Jean
J
Gagnon
Jean-Yves
JY
Cesbron
D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002531:Cerebellum / Q000473:pathology*; D058851:GPI-Linked Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D011328:Prions / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018183:Transplantation Chimera
D058851:GPI-Linked Proteins; D011328:Prions; C122036:Prnd protein, mouse