α-synuclein, especially the parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils

Hilal A. Lashuel, Benjamin M. Petre, Joseph Wall, Martha Simon, Richard J. Nowak, Thomas Walz, Peter T. Lansbury

Research output: Contribution to journalArticle

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Abstract

Two mutations in the α-synuclein gene (A30P and A53T) have been linked to autosomal dominant early-onset Parkinson's disease (PD). Both mutations promote the formation of transient protofibrils (prefibrillar oligomers), suggesting that protofibrils are linked to cytotoxicity. In this work, the effect of these mutations on the structure of α-synuclein oligomers was investigated using electron microscopy and digital image processing. The PD-linked mutations (A30P and A53T) were observed to affect both the morphology and the size distribution of α-synuclein protofibrils (measured by analytical ultracentrifugation and scanning transmission electron microscopy). The A30P variant was observed to promote the formation of annular, pore-like protofibrils, whereas A53T promotes formation of annular and tubular protofibrillar structures. Wild-type α-synuclein also formed annular protofibrils, but only after extended incubation. The formation of pore-like oligomeric structures may explain the membrane permeabilization activity of α-synuclein protofibrils. These structures may contribute to the pathogenesis of PD.

Original languageEnglish
Pages (from-to)1089-1102
Number of pages14
JournalJournal of Molecular Biology
Volume322
Issue number5
DOIs
Publication statusPublished - 14 Nov 2002
Externally publishedYes

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Synucleins
Parkinson Disease
Mutation
Scanning Transmission Electron Microscopy
Ultracentrifugation
Electron Microscopy
Membranes
Genes

Keywords

  • α-synuclein
  • Parkinson's disease
  • Protofibrils
  • Scanning transmission electron microscopy
  • Transmission electron microscopy

ASJC Scopus subject areas

  • Virology

Cite this

α-synuclein, especially the parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils. / Lashuel, Hilal A.; Petre, Benjamin M.; Wall, Joseph; Simon, Martha; Nowak, Richard J.; Walz, Thomas; Lansbury, Peter T.

In: Journal of Molecular Biology, Vol. 322, No. 5, 14.11.2002, p. 1089-1102.

Research output: Contribution to journalArticle

Lashuel, Hilal A. ; Petre, Benjamin M. ; Wall, Joseph ; Simon, Martha ; Nowak, Richard J. ; Walz, Thomas ; Lansbury, Peter T. / α-synuclein, especially the parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils. In: Journal of Molecular Biology. 2002 ; Vol. 322, No. 5. pp. 1089-1102.
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