Research Article

Amyloidogenicity and neurotoxicity of peptides corresponding to the helical regions of PrPC

  1. Andrew Thompson1,
  2. Anthony R. White2,3,
  3. Catriona McLean2,3,
  4. Colin L. Masters2,3,
  5. Roberto Cappai2,3,
  6. Colin J. Barrow1,*

Article first published online: 29 SEP 2000

DOI: 10.1002/1097-4547(20001015)62:2<293::AID-JNR14>3.0.CO;2-Y

Issue

Journal of Neuroscience Research

Journal of Neuroscience Research

Volume 62, Issue 2, pages 293–301, 15 October 2000

Additional Information

How to Cite

Thompson, A., White, A. R., McLean, C., Masters, C. L., Cappai, R. and Barrow, C. J. (2000), Amyloidogenicity and neurotoxicity of peptides corresponding to the helical regions of PrPC. J. Neurosci. Res., 62: 293–301. doi: 10.1002/1097-4547(20001015)62:2<293::AID-JNR14>3.0.CO;2-Y

Author Information

  1. 1

    School of Chemistry, The University of Melbourne, Parkville, Victoria, Australia

  2. 2

    Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia

  3. 3

    The Mental Health Research Institute, Parkville, Victoria, Australia

*School of Chemistry, The University of Melbourne, Parkville, Victoria 3052, Australia

Publication History

  1. Issue published online: 29 SEP 2000
  2. Article first published online: 29 SEP 2000
  3. Manuscript Accepted: 26 JUN 2000
  4. Manuscript Revised: 12 JUN 2000
  5. Manuscript Received: 30 MAR 2000

Funded by

  • Suntory Institute of Bioorganic Research
  • National Health and Medical Research Council of Australia
  • National Pituitary Hormones Advisory Council

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Keywords:

  • amyloid;
  • neurotoxicity;
  • prion;
  • copper;
  • helix;
  • circular dichroism

Abstract

An α-helical to β-sheet conformational change in the prion protein, PrPC, is believed to be causative in transmissible spongiform encephalopathies. Recent nuclear magnetic resonance structures of PrPC have identified three helical regions in the normal full-length protein. We have synthesised peptides corresponding to these helical regions (PrP144-154, helical region one; PrP178-193, helical region two; and PrP198-218, helical region three). Circular dichroism results show that the peptide corresponding to helical region one is unstructured, while peptides corresponding to the second and third helical regions have a high propensity to form β-sheet structure in a pH-dependent manner in aqueous solutions. Peptides corresponding to the second helical region, PrP180-193 and PrP178-193, are the only ones that form amyloid by electron microscopy and congo red birefringence. PrP178-193 and the amyloidogenic Alzheimer's disease Aβ25-25 peptide were found to promote Cu (II)-induced lipid peroxidation and cytotoxicity in primary neuronal cultures, while PrP144-154, PrP198-218 and the nonamyloidogenic Aβ1-28 had no effect on Cu (II) toxicity. There was no increase in toxicity induced by PrP178-193 in cultures treated with Fe (II) or hydrogen peroxide, indicating a preferential modulatory effect on Cu (II) toxicity by PrP178-193. The data suggest that the PrP178-193 peptide has both structural and bioactive properties in common with Aβ25-35 and that the second putative helical region of PrP could be involved in modulation of Cu (II)-mediated toxicity in neurons during prion disease. J. Neurosci. Res. 62:293–301, 2000. © 2000 Wiley-Liss, Inc.

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