Fibrillar deposits of α-synuclein occur in several neurodegenerative diseases. Two mutant forms of α-synuclein have been associated with early-onset Parkinson's disease, and a fragment has been identified as the non-amyloid-β peptide component of Alzheimer's disease amyloid (NAC). Upon aging, solutions of α-synuclein and NAC change conformation to β-sheet, detectable by CD spectroscopy, and form oligomers that deposit as amyloid-like fibrils, detectable by electron microscopy. These aged peptides are also neurotoxic. Experiments on fragments of NAC have enabled the region of NAC responsible for its aggregation and toxicity to be identified. NAC(8–18) is the smallest fragment that aggregates, as indicated by the concentration of peptide remaining in solution after 3 days, and forms fibrils, as determined by electron microscopy. Fragments NAC(8–18) and NAC(8–16) are toxic, whereas NAC(12–18), NAC(9–16) and NAC(8–15) are not. Hence residues 8–16 of NAC comprise the region crucial for toxicity. Toxicity induced by α-synuclein, NAC and NAC(1–18) oligomers occurs via an apoptotic mechanism, possibly initiated by oxidative damage, since these peptides liberate hydroxyl radicals in the presence of iron. Molecules with anti-aggregational and/or antioxidant properties may therefore be potential therapeutic agents.
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Conference Article|
August 01 2002
Aggregation and neurotoxicity of α-synuclein and related peptides
O. M. A. EI-Agnaf;
O. M. A. EI-Agnaf
1
*Department of Biological Sciences, Lancaster University, Lancaster LA1 4YQ, U.K.
1To whom correspondence should be addressed (e-mail o.el-agnaf@lancaster.ac.uk)
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G. B. Irvine
G. B. Irvine
†Neuroscience Research Group, School of Biology and Biochemistry, Queen's University Belfast, Medical Biology Centre, Belfast BT9 7BL, U.K.
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Publisher: Portland Press Ltd
Received:
April 10 2002
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2002 Biochemical Society
2002
Biochem Soc Trans (2002) 30 (4): 559–565.
Article history
Received:
April 10 2002
Citation
O. M. A. EI-Agnaf, G. B. Irvine; Aggregation and neurotoxicity of α-synuclein and related peptides. Biochem Soc Trans 1 August 2002; 30 (4): 559–565. doi: https://doi.org/10.1042/bst0300559
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