alpha-synuclein: amyloid fibrils and interactions with lipid membranes
Author
Summary, in English
The second most common neurodegenerative disease, Parkinson’s disease, is linked with an amyloid forming protein, alpha-synuclein. Hallmarks of Parkinson’s disease are progressive loss of dopaminergic neurons and accumulation of intraneuronal inclusions termed Lewy bodies. Major components of Lewy bodies are amyloid fibrils formed by alpha-synuclein and various lipids and cell organelles.
In this thesis, we investigated the interaction of alpha-synuclein and different model lipid membranes. The main techniques have been small-angle neutron scattering (SANS) and small-angle X-ray scattering (SAXS). We focused on the structure of alpha-synuclein fibrils and model lipid membranes, both alone and when in the presence of each other. The investigations were performed when the protein was present both in its monomeric and fibrillar form. We also studied fibril formation process in the presence of model membranes and followed the effect it has on the membrane structure, as well as the effect membranes have on the structure of mature fibrils. Finally, we investigated arrangement of colloidally unstable alpha-synuclein fibrils and their interaction with various lipid membranes.
We learned that interaction of monomeric alpha-synuclein and lipid disc micelles results in a major deformation of the disc shape, but that the partial recovery is possible due to the desorption of monomers and their incorporation into amyloid fibrils. We also learned that the fibril formation can cause vesicle fusion. The presence of model membranes during the fibril formation has no effect on the cross-sectional size and structure of fibrils, nor is there any observable incorporation of lipid molecules into the mature fibrils. The colloidally unstable alpha-synuclein fibrils arrange into mass clusters, independent on the presence of different lipid vesicles, and this arrangement is reproduced with a simple rigid-rod cluster model.
In this thesis, we investigated the interaction of alpha-synuclein and different model lipid membranes. The main techniques have been small-angle neutron scattering (SANS) and small-angle X-ray scattering (SAXS). We focused on the structure of alpha-synuclein fibrils and model lipid membranes, both alone and when in the presence of each other. The investigations were performed when the protein was present both in its monomeric and fibrillar form. We also studied fibril formation process in the presence of model membranes and followed the effect it has on the membrane structure, as well as the effect membranes have on the structure of mature fibrils. Finally, we investigated arrangement of colloidally unstable alpha-synuclein fibrils and their interaction with various lipid membranes.
We learned that interaction of monomeric alpha-synuclein and lipid disc micelles results in a major deformation of the disc shape, but that the partial recovery is possible due to the desorption of monomers and their incorporation into amyloid fibrils. We also learned that the fibril formation can cause vesicle fusion. The presence of model membranes during the fibril formation has no effect on the cross-sectional size and structure of fibrils, nor is there any observable incorporation of lipid molecules into the mature fibrils. The colloidally unstable alpha-synuclein fibrils arrange into mass clusters, independent on the presence of different lipid vesicles, and this arrangement is reproduced with a simple rigid-rod cluster model.
Department/s
Publishing year
2021
Language
English
Full text
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Document type
Dissertation
Publisher
Lund University
Topic
- Physical Chemistry
Keywords
- alpha-synuclein
- model lipid membranes
- amyloid fibrils
- Parkinson's disease
- Lewy bodies
- SANS
- SAXS
Status
Published
Supervisor
ISBN/ISSN/Other
- ISBN: 978-91-7422-841-0
- ISBN: 978-91-7422-840-3
Defence date
16 December 2021
Defence time
13:00
Defence place
Kemicentrum KC:A, Lund. Join via Zoom: https://lu-se.zoom.us/j/64263865014/ or Live-streaming channel: https://www.youtube.com/channel/UCnuD6zyuQ4vwg9zSBeTQoQQ/featured
Opponent
- Raffaele Mezzenga (Professor)