TAILIEUCHUNG - Báo cáo Y học: Toxicity of novel C-terminal prion protein fragments and peptides harbouring disease-related C-terminal mutations

Mice expressing a C-terminal fragment of the prion protein instead of wild-type prion protein die from massive neuronal degeneration within weeks of birth. The C-terminal region of PrPc (PrP121–231) expressed in these mice has an intrinsic neurotoxicity to cultured neurones. Unlike PrPSc, which is not neurotoxic to neurones lacking PrPc expression, PrP121–231 was more neurotoxic to PrPc-deficient cells. Human mutations E200K and F198S were found to enhance toxicity of PrP121–231 to PrP-knockout neurones and E200K enhanced toxicity to wild-type neurones. The normal metabolic cleavage point of PrPc is approximately aminoacid residue 113. A fragment of PrPc corresponding to the whole. | Eur. J. Biochem. 268 6155-6164 2001 FEBS 2001 Toxicity of novel C-terminal prion protein fragments and peptides harbouring disease-related C-terminal mutations Maki Daniels1 Grazia Maria Cereghetti2 and David R. Brown1 1 Department of Biochemistry Cambridge University UK 2 Institute of Molecular Biology and Biophysics ETH-Hoeneggerberg Zurich Switzerland Mice expressing a C-terminal fragment of the prion protein instead of wild-type prion protein die from massive neuronal degeneration within weeks of birth. The C-terminal region of PrPc PrP121-231 expressed in these mice has an intrinsic neurotoxicity to cultured neurones. Unlike PrPSc which is not neurotoxic to neurones lacking PrPc expression PrP121-231 was more neurotoxic to PrPc-deficient cells. Human mutations E200K and F198S were found to enhance toxicity of PrP121-231 to PrP-knockout neurones and E200K enhanced toxicity to wild-type neurones. The normal metabolic cleavage point of PrPc is approximately aminoacid residue 113. A fragment of PrPc corresponding to the whole C-terminus of PrPc PrP113-231 which is eight amino acids longer than PrP121-231 lacked any toxicity. This suggests the first eight amino residues of PrP113-121 suppress toxicity of the toxic domain in PrP121 - 231. Addition to cultures of a peptide PrP112-125 corresponding to this region in parallel with PrP121-231 suppressed the toxicity of PrP121 - 231. These results suggest that the prion protein contains two domains that are toxic on their own but which neutralize each other s toxicity in the intact protein. Point mutations in the inherited forms of disease might have their effects by diminishing this inhibition. Keywords prion neurotoxicity circular dichroism neurodegeneration. PrPc is a normal cell surface glycoprotein expressed by many cells including neurones and astrocytes 1-3 microglia 4 oligodendroglia 2 leukocytes 5 and muscle cells 6 . PrPc is attached to the cell membrane via a GPI glycophosphoinositol anchor 7 . Predominantly .

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