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Investigating the Role of 14-3-3 Proteins in Multiple Stages of Multimerization and Aggregation of α-Synuclein
Heidema, Christel G. (2025) Investigating the Role of 14-3-3 Proteins in Multiple Stages of Multimerization and Aggregation of α-Synuclein.
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| Abstract: | Parkinson’s disease, a neurodegenerative disorder, is associated with the aggregation of the intrinsically disordered protein α-synuclein (αS). A family of proteins known as 14-3-3 chaperones, which are part of the cellular protein quality control system, have shown an inhibiting role in aggregation of αS. However, the way in which these chaperones interact with αS remains poorly understood. This study investigates both the early multimerization stages of α-synuclein and the later fibrillar stages of αS aggregation, focusing on interactions with 14-3-3 at these different stages. Using Microscale Thermophoresis (MST) measurements, this study demonstrates that αS multimerizes in early stage through a cooperative mechanism. This study revealed that electrostatic interactions and hydrogen bonds play a crucial role in early αS multimerization. The τ , γ, and σ isoforms of 14-3-3 all affect this early αS multimerization, overall resulting in a decrease in cooperativity. This may indicate the formation of mixed multimers of αS and 14-3-3 through a non-cooperative process. These mixed multimers do not form amyloid fibrils and compete with the formation of fibrils from αS-only multimers. Using the techniques Microscale Thermophoresis (MST) and Fluorescence Correlation Spectroscopy (FCS), indications for interaction between αS 30-mers and 14-3-3τ were found. In combination with the MST results of early multimerization, this indicates that 14-3-3τ does not interact with a specific αS multimer or size, but rather exhibits a more general interaction. Additionally, colocalization in confocal imaging and MST experiment suggest that 14-3-3τ binds to αS fibrils. These insights enhance the understanding of how 14-3-3 proteins modulate αS aggregation and may support the development of new therapeutic approaches for Parkinson’s disease. |
| Item Type: | Essay (Master) |
| Faculty: | TNW: Science and Technology |
| Subject: | 33 physics, 42 biology |
| Programme: | Biomedical Engineering MSc (66226) |
| Link to this item: | https://purl.utwente.nl/essays/107760 |
| Export this item as: | BibTeX EndNote HTML Citation Reference Manager |
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