Aggregation and neurotoxicity of α-synuclein and related peptides

Omar Ali El-Agnaf, G. B. Irvine

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

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 antiaggregational and/or antioxidant properties may therefore be potential therapeutic agents.

Original languageEnglish
Pages (from-to)559-565
Number of pages7
JournalBiochemical Society Transactions
Volume30
Issue number4
DOIs
Publication statusPublished - Aug 2002
Externally publishedYes

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Synucleins
Agglomeration
Toxicity
Peptides
Oligomers
Amyloid
Electron microscopy
Electron Microscopy
Deposits
Neurodegenerative diseases
Poisons
Neurodegenerative Diseases
Hydroxyl Radical
Parkinson Disease
Conformations
Spectrum Analysis
Alzheimer Disease
Iron
Antioxidants
Aging of materials

Keywords

  • Amyloid
  • Fibril
  • Parkinson's disease

ASJC Scopus subject areas

  • Biochemistry

Cite this

Aggregation and neurotoxicity of α-synuclein and related peptides. / Ali El-Agnaf, Omar; Irvine, G. B.

In: Biochemical Society Transactions, Vol. 30, No. 4, 08.2002, p. 559-565.

Research output: Contribution to journalArticle

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