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

Zoltan Nemes, G Petrovski, Maarten Aerts UGent, Kjell Sergeant, Bart Devreese UGent and Lazslo Fesus (2009) Journal of Biological Chemistry. 284. p.27252-27264
abstract
The alpha-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 gamma-glutamyl-epsilon-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 alpha-synuclein was found, and it contained a low amount of intramolecular cross-links between Gln-99 and Lys-58. In vitro cross-linking of alpha-synuclein by transglutaminases 1-3 and 5 produced a heterogeneous population of variably cross-linked alpha-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 alpha-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 alpha-synuclein.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
journal title
Journal of Biological Chemistry
J. Biol. Chem.
volume
284
pages
27252 - 27264
Web of Science type
Article
Web of Science id
000270232300026
JCR category
BIOCHEMISTRY & MOLECULAR BIOLOGY
JCR impact factor
5.328 (2009)
JCR rank
48/281 (2009)
JCR quartile
1 (2009)
ISSN
0021-9258
DOI
10.1074/jbc.M109.033969
language
English
UGent publication?
yes
classification
A1
id
864703
handle
http://hdl.handle.net/1854/LU-864703
date created
2010-02-16 16:38:15
date last changed
2010-03-04 11:36:26
@article{864703,
  abstract     = {The alpha-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 gamma-glutamyl-epsilon-lysine bonds between HspB1 and ubiquitin in a pattern similar to neurofibrillary tangles (Nemes, Z., Devreese, B., Steinert, P. M., Van Beeumen, J., and F{\'e}s{\"u}s, L. (2004) FASEB J. 18, 1135-1137), 53 proteins were identified. In the core of Lewy bodies only alpha-synuclein was found, and it contained a low amount of intramolecular cross-links between Gln-99 and Lys-58. In vitro cross-linking of alpha-synuclein by transglutaminases 1-3 and 5 produced a heterogeneous population of variably cross-linked alpha-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 alpha-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 alpha-synuclein.},
  author       = {Nemes, Zoltan and Petrovski, G and Aerts, Maarten and Sergeant, Kjell  and Devreese, Bart and Fesus, Lazslo},
  issn         = {0021-9258},
  journal      = {Journal of Biological Chemistry},
  language     = {eng},
  pages        = {27252--27264},
  title        = {Transglutaminase-mediated intramolecular cross-linking of membrane-bound \{alpha\}-synuclein promotes amyloid formation in Lewy bodies},
  url          = {http://dx.doi.org/10.1074/jbc.M109.033969},
  volume       = {284},
  year         = {2009},
}

Chicago
Nemes, Zoltan, G Petrovski, Maarten Aerts, Kjell Sergeant, Bart Devreese, and Lazslo Fesus. 2009. “Transglutaminase-mediated Intramolecular Cross-linking of Membrane-bound {alpha}-synuclein Promotes Amyloid Formation in Lewy Bodies.” Journal of Biological Chemistry 284: 27252–27264.
APA
Nemes, Zoltan, Petrovski, G., Aerts, M., Sergeant, K., Devreese, B., & Fesus, L. (2009). Transglutaminase-mediated intramolecular cross-linking of membrane-bound {alpha}-synuclein promotes amyloid formation in Lewy bodies. Journal of Biological Chemistry, 284, 27252–27264.
Vancouver
1.
Nemes Z, Petrovski G, Aerts M, Sergeant K, Devreese B, Fesus L. Transglutaminase-mediated intramolecular cross-linking of membrane-bound {alpha}-synuclein promotes amyloid formation in Lewy bodies. Journal of Biological Chemistry. 2009;284:27252–64.
MLA
Nemes, Zoltan, G Petrovski, Maarten Aerts, et al. “Transglutaminase-mediated Intramolecular Cross-linking of Membrane-bound {alpha}-synuclein Promotes Amyloid Formation in Lewy Bodies.” Journal of Biological Chemistry 284 (2009): 27252–27264. Print.