Neurotoxicity of prion peptides mimicking the central domain of the cellular prion protein.
The physiological functions of PrP(C) remain enigmatic, but the central domain, comprising highly conserved regions of the protein may play an important role. Indeed, a large number of studies indicate that synthetic peptides containing residues 106-126 (CR) located in the central domain (CD, 95-133) of PrP(C) are neurotoxic. The central domain comprises two chemically distinct subdomains, the charge cluster (CC, 95-110) and a hydrophobic region (HR, 112-133). The aim of the present study was to establish the individual cytotoxicity of CC, HR and CD. Our results show that only the CD peptide is neurotoxic. Biochemical, Transmission Electron Microscopy and Atomic Force Microscopy experiments demonstrated that the CD peptide is able to activate caspase-3 and disrupt the cell membrane, leading to cell death.
Molecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia, Barcelona, Spain.
Silvia
S
Vilches
Cristina
C
Vergara
Oriol
O
Nicolás
Gloria
G
Sanclimens
Sandra
S
Merino
Sonia
S
Varón
Gerardo A
GA
Acosta
Fernando
F
Albericio
Miriam
M
Royo
José A
JA
Del Río
Rosalina
R
Gavín
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D052160:Benzothiazoles; D053148:Caspase 3 / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry; D004789:Enzyme Activation; D005456:Fluorescent Dyes / Q000737:chemistry; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D018621:PrPC Proteins / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D061251:Primary Cell Culture; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D013844:Thiazoles / Q000737:chemistry
D052160:Benzothiazoles; D005456:Fluorescent Dyes; D008051:Lipid Bilayers; D010446:Peptide Fragments; D018621:PrPC Proteins; D013844:Thiazoles; C009462:thioflavin T; C505409:Casp3 protein, mouse; D053148:Caspase 3; D004134:Dimyristoylphosphatidylcholine