Journal article:
Proteolytic intermediates in the oligomerisation-aggregation pathway of alpha-synuclein revealed by ion mobility mass spectrometry

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2010
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A variety of diseases, previously thought to be unrelated, such as cancer and neurodegenerative diseases, are characterised by the formation of ”misfolded”protein aggregates. While ”soft-ionisation”mass spectrometry (MS), particularly electrospray-MS (ESI-MS), has substantially contributed to peptide analysis and proteomics, ESI-MS is not suitable to direct ”in-situ”analysis of conformational states and intermediates. Recently, ion mobility mass spectrometry (IM-MS) is emerging as a new tool to probe protein structures and interactions due to its potential for separation polypeptides by conformational states, shape and topology. We report here first applications of IM-MS to the characterization of reaction intermediates in the in vitro oligomerisation and aggregation of alpha-synuclein (αSyn), a key polypeptide in Parkinson’s disease. IM-MS of the in vitro aggregation of wt-αSyn enabled the structure elucidation of several hitherto unknown N- and C-terminal products, and a proteolytic fragment at V71-T72 in the aggregation domain (C-VT72; 7.2 kDa), which appears to be a key intermediate in the aggregation pathway; in vitro studies of this fragment prepared by chemical synthesis and bacterial expression showed a dramatically enhanced rate of aggregation. Most recently, IM-MS was also successfully applied to the direct analysis of affinity-captured αSyn from biological samples, such as brain homogenate, indicating this method as a powerful new tool to the molecular characterization of conformation-dependant intermediates of protein aggregation.
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570 Biosciences, Biology
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Journal of Peptide Science ; 16 (2010), S1. - pp. 43. - Wiley. - ISSN 1075-2617. - eISSN 1099-1387
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ISO 690PRZYBYLSKI, Michael, Camelia VLAD, Kathrin LINDNER, Thomas CIOSSEK, Bastian HENGERER, Marcel LEIST, 2010. Proteolytic intermediates in the oligomerisation-aggregation pathway of alpha-synuclein revealed by ion mobility mass spectrometry. In: Journal of Peptide Science. Wiley. 16(S1), pp. 43. ISSN 1075-2617. eISSN 1099-1387. Available under: doi: 10.1002/psc.1301
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@article{Przybylski2010Prote-52627,
  year={2010},
  doi={10.1002/psc.1301},
  title={Proteolytic intermediates in the oligomerisation-aggregation pathway of alpha-synuclein revealed by ion mobility mass spectrometry},
  number={S1},
  volume={16},
  issn={1075-2617},
  journal={Journal of Peptide Science},
  author={Przybylski, Michael and Vlad, Camelia and Lindner, Kathrin and Ciossek, Thomas and Hengerer, Bastian and Leist, Marcel},
  note={Meeting Abstract}
}
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