Dominant-negative effects of the N-terminal half of prion protein on neurotoxicity of prion protein-like protein/doppel in mice.
Prion protein-like protein/doppel is neurotoxic, causing ataxia and Purkinje cell degeneration in mice, whereas prion protein antagonizes doppel-induced neurodegeneration. Doppel is homologous to the C-terminal half of prion protein but lacks the amino acid sequences corresponding to the N-terminal half of prion protein. We show here that transgenic mice expressing a fusion protein consisting of the N-terminal half, corresponding to residues 1-124, of prion protein and doppel in neurons failed to develop any neurological signs for up to 730 days in a background devoid of prion protein. In addition, the fusion protein prolonged the onset of ataxia in mice expressing exogenous doppel. These results suggested that the N-terminal part of prion protein has a neuroprotective potential acting both cis and trans on doppel. We also show that prion protein lacking the pre-octapeptide repeat (Delta25-50) or octapeptide repeat (Delta51-90) region alone could not impair the antagonistic function against doppel.
Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki.
Daisuke
D
Yoshikawa
Naohiro
N
Yamaguchi
Daisuke
D
Ishibashi
Hitoki
H
Yamanaka
Nobuhiko
N
Okimura
Yoshitaka
Y
Yamaguchi
Tsuyoshi
T
Mori
Hironori
H
Miyata
Kazuto
K
Shigematsu
Shigeru
S
Katamine
Suehiro
S
Sakaguchi
D000818:Animals; D001259:Ataxia / Q000378:metabolism* / Q000473:pathology; D058851:GPI-Linked Proteins; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D011328:Prions / Q000096:biosynthesis* / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis* / Q000235:genetics
D058851:GPI-Linked Proteins; D011328:Prions; C122036:Prnd protein, mouse; D011993:Recombinant Fusion Proteins