Dokument: Investigation of oligomerization of amyloid-β and prion protein

Titel:	Investigation of oligomerization of amyloid-β and prion protein
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=61470
URN (NBN):	urn:nbn:de:hbz:061-20230109-103211-7
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Pauly, Thomas [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 41,75 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 12.12.2022 / geändert 12.12.2022
Beitragende:	Prof.Dr. Willbold Dieter [Gutachter] Dr. Hoyer, Wolfgang [Gutachter]
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie
Beschreibung:	Neurodegenerative diseases like Alzheimer’s Disease and prion diseases involve abnormal accumulation of misfolded proteins in the brain, like the Amyloid-β (Aβ) peptide or the prion protein (PrP). These proteins adopt typical cross-β-sheet conformation to assemble into highly ordered amyloid fibrils. Oligomeric intermediates are central to the study of disease-related aggregation mechanisms, so their detailed characterization may offer new therapeutic targets. However, the dynamic nature and overall low concentration of oligomeric intermediates impede their proper characterization. For the Aβ peptide, three different oligomeric species were identified in the course of amyloid formation using sedimentation velocity analysis. The comparison of three natural variants of the Aβ peptide, Aβ42, Aβ40, and Aβ42 M35ox, allowed to infer different contributions of these oligomers to the mechanism of amyloid formation. Small oligomeric species, with sizes corresponding to trimers to hexamers, were identified with constant sedimentation coefficient in all three Aβ variants throughout the entire aggregation process. Larger oligomeric species represent a heterogeneous population with sizes of approximately 35 to 47 monomeric units per assembly. This group of oligomers increases in weighted average s-value during the lag phase of amyloid formation, indicating an increasing number of monomeric units to approximately 78 to 89 per assembly before amyloid growth was observed. These larger oligomers present high local monomer concentrations, lowering the energetic barrier for the formation of a nucleus capable of forming amyloid. For the three variants of the Aβ peptide, the concentration of larger oligomers inversely correlates with the time required for amyloid formation, indicating an aggregation mechanism at least partially mediated by oligomeric intermediates. Human PrP has a naturally occurring polymorphism at position 129, which relates to different pathologies and susceptibility to prion diseases. This polymorphism results in two variants, either 129M or 129V. Here, differences in the tendency to form oligomers and corresponding differences in the mechanism of amyloid formation were demonstrated. The 129M variant is more prone to oligomerization and amyloid formation includes multiphasic behavior with interim plateaus. In contrast, the 129V variant is predominantly monomeric and amyloid formation directly proceeds to the final plateau. In contrast to unstructured Aβ, the secondary structure of huPrP must be destabilized to enable conversion into amyloid structure. Therefore, the amyloid formation of the 129V variant presumably starts from a destabilized monomer, while the 129M variant involves oligomeric intermediates that undergo structural conversion to reach the final amyloid structure. It was concluded that the polymorphism at position 129 dictates distinct pathways of amyloid formation, which is associated with different disease pathologies. In this work, different mechanisms of amyloid formation were studied, focusing on the role of oligomerization. The successful characterization of distinct oligomeric species of natural Aβ and huPrP variants will improve the understanding of disease related aggregation mechanisms. Specific oligomeric species were shown to be on-pathway to amyloid formation by revealing their impact on the aggregation pathway. The influence of oligomers on amyloid formation can be linked to differences in disease pathology. The identified oligomers thus provide valuable insights into the aggregation mechanisms underlying the diseases and represent potential targets to interfere with the amyloid formation process.
Lizenz:	Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz
Fachbereich / Einrichtung:	Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie » Physikalische Biologie
Dokument erstellt am:	09.01.2023
Dateien geändert am:	09.01.2023
Promotionsantrag am:	29.09.2022
Datum der Promotion:	07.12.2022