Aggregation and neurotoxicity of alpha-synuclein and related peptides

Fibrillar deposits of alpha-synuclein occur in several neurodegenerative diseases. Two mutant forms of alpha-synuclein have been associated with early-onset Parkinson's disease, and a fragment has been identified as the non-amyloid-beta peptide component of Alzheimer's disease amyloid (NAC...

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Bibliographic Details
Published inBiochemical Society transactions Vol. 30; no. 4; p. 559
Main Authors el-Agnaf, O M A, Irvine, G B
Format Journal Article
LanguageEnglish
Published England 01.08.2002
Subjects
alpha-Synuclein
Alzheimer Disease - pathology
Animals
Brain - pathology
Cell Survival - drug effects
Humans
Molecular Weight
Nerve Tissue Proteins - chemistry
Nerve Tissue Proteins - toxicity
Neurotoxins - chemistry
Neurotoxins - toxicity
PC12 Cells
Phosphoproteins - chemistry
Phosphoproteins - toxicity
Protein Conformation
Protein Structure, Secondary
Rats
Synucleins
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Summary:Fibrillar deposits of alpha-synuclein occur in several neurodegenerative diseases. Two mutant forms of alpha-synuclein have been associated with early-onset Parkinson's disease, and a fragment has been identified as the non-amyloid-beta peptide component of Alzheimer's disease amyloid (NAC). Upon aging, solutions of alpha-synuclein and NAC change conformation to beta-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 alpha-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.
ISSN:0300-5127
DOI:10.1042/BST0300559