A synthetic peptide initiates Gerstmann-Sträussler-Scheinker (GSS) disease in transgenic mice.
The molecular basis of the infectious, inherited and sporadic forms of prion diseases is best explained by a conformationally dimorphic protein that can exist in distinct normal and disease-causing isoforms. We identified a 55-residue peptide of a mutant prion protein that can be refolded into at least two distinct conformations. When inoculated intracerebrally into the appropriate transgenic mouse host, 20 of 20 mice receiving the beta-form of this peptide developed signs of central nervous system dysfunction at approximately 360 days, with neurohistologic changes that are pathognomonic of Gerstmann-Sträussler-Scheinker disease. By contrast, eight of eight mice receiving a non-beta-form of the peptide failed to develop any neuropathologic changes more than 600 days after the peptide injections. We conclude that a chemically synthesized peptide refolded into the appropriate conformation can accelerate or possibly initiate prion disease.
Kaneko
K
K
Institute for Neurodegenerative Diseases, Department of Neurology, University of California, San Francisco, 94143, USA.
Ball
H L
HL
Wille
H
H
Zhang
H
H
Groth
D
D
Torchia
M
M
Tremblay
P
P
Safar
J
J
Prusiner
S B
SB
DeArmond
S J
SJ
Baldwin
M A
MA
Cohen
F E
FE
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D016098:Gerstmann-Straussler-Scheinker Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity; D011328:Prions / Q000737:chemistry / Q000235:genetics*; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012608:Scrapie / Q000473:pathology; D017550:Spectroscopy, Fourier Transform Infrared
D010446:Peptide Fragments; D011328:Prions