Dokument: Biophysikalische Charakterisierung der spontanen und keiminduzierten Fibrillogenese des humanen Prion-Proteins im Hinblick auf die Untersuchung der Speziesbarriere
| Titel: | Biophysikalische Charakterisierung der spontanen und keiminduzierten Fibrillogenese des humanen Prion-Proteins im Hinblick auf die Untersuchung der Speziesbarriere | |||||||
| Weiterer Titel: | Biophysical Characterisation of Spontaneous and Seeded Fibrillogenesis of the Human Prion Protein in Respect of the Analysis of the Species Barrier | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=25677 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20130514-150541-4 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Dr. Lüers, Lars [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Willbold, Dieter [Betreuer/Doktorvater] Prof. Dr. Georg Groth [Gutachter] | |||||||
| Stichwörter: | prion, SDS, protein aggregation, ThT, CJD, BSE | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibungen: | Ein besonderes Merkmal einiger neurodegenerativer Erkrankungen ist die Aggregation körpereigener Proteine im zentralen Nervensystem. Die Prionkrankheiten bilden dabei eine gesonderte Gruppe, da sie auf natürlichem Wege übertragbar sind. Prionkrankheiten sind nicht nur innerhalb einer Spezies übertragbar, sondern können auch zwischen einigen Spezies über die Artgrenze übertragen werden. Bei der interspezifischen Übertragung kann zwischen einigen Spezies eine ausgeprägte Speziesbarriere beobachtet werden. Dies äußert sich bei experimentellen Studien zur Übertragbarkeit z.B. in verlängerten Inkubationszeiten oder dadurch, dass nicht alle oder sogar keines der Versuchstiere eine Prionkrankheit entwickelt. Zwischen anderen Spezies kann die Speziesbarriere eine geringe Ausprägung aufweisen, sodass die Inkubationszeiten denen einer intraspezifischen Übertragung entsprechen.
Um die Speziesbarriere der Prionkrankheiten auf molekularer Ebene zu erforschen, wurde ein in vitro Konversionssystem etabliert, welches auf der Fibrillogenese von rekombinantem humanen Prion-Protein (huPrP) beruht. Die Etablierung und Charakterisierung der spontanen Fibrillogenese des huPrP schaffte die Voraussetzungen für die Etablierung des keiminduzierten Konversionssystems auf Basis von huPrP in Kombination mit natürlichen Prion-Keimen. Mit Hilfe des keiminduzierten Konversionssystems wurde innerhalb dieser Arbeit die Speziesbarriere durch den Einsatz von Keimen aus Hirngewebe der Spezies Rind, Schaf, Hirsch und Mensch mechanistisch analysiert. Die im in vitro Konversionssystems beobachtete Beschleunigung der Fibrillogenese des huPrP, die durch Keime verschiedener Spezies verursacht werden kann, wird als Keim-Aktivität quantifiziert. Durch den Vergleich der Keim-Aktivität innerhalb des in vitro Konversionssystems von Keimen der Spezies Mensch, Rind und Schaf konnte eine Übereinstimmung mit der durch epidemiologische Daten und in vivo Experimente belegten natürlich vorkommende Übertragbarkeit zwischen diesen Spezies gezeigt werden. Ebenso konnte die in der Literatur vermutete Speziesbarriere zwischen den Spezies Hirsch und Mensch durch eine geringe Keim Aktivität innerhalb des in vitro Konversionssystems bestätigt werden. Die exakte Übereinstimmung der Daten aus den in vitro Experimenten innerhalb dieser Arbeit mit existierenden Daten zur natürlich auftretenden Übertragbarkeit ermöglicht es, Rückschlüsse auf den molekularen Mechanismus der Speziesbarriere zu ziehen. Da das hier verwendete in vitro Konversionssystem nur rekombinantes Prion-Protein als Substrat und vorgereinigte und konzentrierte Prion-Keime aus infektiösem Hirngewebe verwendet, kann gezeigt werden, dass die Speziesbarriere einzig mit einer Interaktion von Keim und Substrat erklärt werden kann. Prion diseases are transmissible spongiform encephalopathies in humans and animals, including scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in deer and Creutzfeldt-Jakob disease (CJD) in humans. The hallmark of prion diseases is the conversion of the host-encoded prion protein (PrPC) to its pathological isoform PrPSc, which is accompanied by PrP fibrillation. Transmission of prion disease is not restricted within one species, but can also occur between species. In some cases a strong species barrier can be observed, which results in limited or unsuccessful experimental transmission. The mechanism behind interspecies transmissibility or species barriers is not completely understood. To analyse this process at a molecular level, an in vitro fibrillation assay was established, on the basis of recombinant human PrP (huPrP). Based on this de novo fibrillation assay a seeded in vitro fibrillation assay was established, which can be specifically seeded by prion seeds. By the application of this seeded fibrillation assay, the interspecies transmission to humans was analysed, combining seeds from species cattle, sheep and deer (BSE, scrapie, CWD) with huPrP. The results are in clear agreement with epidemiology, in vitro aggregation studies and bioassays investigating the transmission between humans, cattle, sheep and deer. In contrast to CJD and BSE seeds, which show a high seeding activity, a strong species barrier for seeds from scrapie and CWD is demonstrated within the in vitro fibrillation assay. The assay only requires pure recPrP as substrate and pre-purified prion seeds as. Therefore the seeding phenomenon with purified components and any seeding activity should be based on a direct interaction of seed and substrate. Therefore it is hypothesised that the species barrier is based on the interaction of PrPC and PrPSc. It is shown, that the seeding activity and therewith the molecular interaction of PrP as substrate and PrPSc as seed is sufficient to explain the phenomenon of species barriers. | |||||||
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| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie » Physikalische Biologie | |||||||
| Dokument erstellt am: | 14.05.2013 | |||||||
| Dateien geändert am: | 14.05.2013 | |||||||
| Promotionsantrag am: | 14.03.2013 | |||||||
| Datum der Promotion: | 23.04.2013 |
