Transglutaminase-mediated intramolecular cross-linking of membrane-bound α-synuclein promotes amyloid formation in Lewy bodies

Zoltán Nemes, Goran Petrovski, Maarten Aerts, Kjell Sergeant, Bart Devreese, László Fésüs

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The α-synuclein immunopositive and chaotrope-insoluble material from human brains with Lewy body pathology was analyzed by mass spectrometry. From the proteinase K-cleavable peripheral fraction of Lewy bodies, which was densely cross-linked by γ-glutamyl-ε-lysine bonds between HspB1 and ubiquitin in a pattern similar to neurofibrillary tangles (Nemes, Z., Devreese, B., Steinert, P. M., Van Beeumen, J., and Fésüs, L. (2004) FASEB J. 18, 1135-1137), 53 proteins were identified. In the core of Lewy bodies only α-synuclein was found, and it contained a low amount of intramolecular cross-links between Gln-99 and Lys-58. In vitro cross-linking of α-synuclein by transglutaminases 1-3 and 5 produced a heterogeneous population of variably cross-linked α-synucleins in solution, which inhibited the aggregation of the protein into amyloid. However, in the presence of phosphatidylserine-rich membranes and micromolar calcium concentrations, the cross-linking by transglutaminases 1, 2, and 5 showed specificity toward the utilization of Gln-99 and Lys-58. As shown by thioflavin T fluorescence monitoring, the formation of this cross-link accelerated the aggregation of native α-synuclein. Chemical cross-linking of residues 58-99 triggered amyloid formation, whereas such bonding of residues 99 to 10 was inhibitory. Our findings reveal the pivotal role of membrane attachment and transglutaminase-mediated intermolecular cross-linking for the propagative misfolding and aggregation of α-synuclein.

Original languageEnglish
Pages (from-to)27252-27264
Number of pages13
JournalJournal of Biological Chemistry
Volume284
Issue number40
DOIs
Publication statusPublished - Oct 2 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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