NR AECL
AU Forloni,G.; Angeretti,N.; Chiesa,R.; Monzani,E.; Salmona,M.; Bugiani,O.; Tagliavini,F.
TI Neurotoxicity of a prion protein fragment
QU Nature 1993 Apr 8; 362(6420): 543-6
PT journal article
AB The cellular prion protein (PrPc) is a sialoglycoprotein of M(r) 33-35K that is expressed predominantly in neurons. In transmissible and genetic neurodegenerative disorders such as scrapie of sheep, spongiform encephalopathy of cattle and Creutzfeldt-Jakob or Gerstmann-Sträussler-Scheinker diseases of humans, PrPc is converted into an altered form (termed PrPsc) which is distinguishable from its normal homologue by its relative resistance to protease digestion. PrPsc accumulates in the central nervous system of affected individuals, and its protease-resistant core aggregates extracellularly into amyloid fibrils. The process is accompanied by nerve cell loss, whose pathogenesis and molecular basis are not understood. We report here that neuronal death results from chronic exposure of primary rat hippocampal cultures to micromolar concentrations of a peptide corresponding to residues 106-126 of the amino-acid sequence deduced from human PrP complementary DNA. DNA fragmentation of degenerating neurons indicates that cell death occurred by apoptosis. The PrP peptide 106-126 has a high intrinsic ability to polymerize into amyloid-like fibrils in vitro. These findings indicate that cerebral accumulation of PrPsc and its degradation products may play a role in the nerve cell degeneration that occurs in prion-related encephalopathies.
IN Das normale Prionprotein ist ein vorwiegend in Neuronen exprimiertes Sialoglycoprotein mit einem scheinbaren Molekulargewicht von 33-35 Kilodalton. In den vererbten oder durch Infektionen erworbenen Erkrankung des zentralen Nervensystems, Scrapie beim Schaf, BSE bei Rindern und Creutzfeldt-Jakob oder Gerstmann-Sträussler-Scheinker des Menschen akkumuliert das Prionprotein in einer proteaserestenteren Form. Diese Aggregate wachsen auch extrazellulär in Form amyloider Fibrillen und irgendwie sterben die umgebenden Nervenzellen. Kultivierte Neuronen können auch durch in mikromolaren Konzentrationen dem Medium über längere Zeit zugegebene, den Aminosäuren 106-126 des Prionproteins entsprechende synthetische Peptide getötet werden. Diese kleinen Peptide können in vitro zu amyloidartigen Fibrillen polymerisieren.
MH Amino Acid Sequence; Animal; Apoptosis; Cells, Cultured; Dose-Response Relationship, Drug; Hippocampus/cytology/metabolism; Molecular Sequence Data; Neurons/*drug effects; Peptide Fragments/genetics/*toxicity; Prions/*toxicity; Rats; Support, Non-U.S. Gov't
AD Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
SP englisch
PO England