Investigating Synthetic Approaches of the Neuroregulator α-Synuclein
by Clara Bosbach
Date of Examination:2023-12-07
Date of issue:2024-01-04
Advisor:Prof. Dr. Claudia Steinem
Referee:Prof. Dr. Claudia Steinem
Referee:Prof. Dr. Tiago Fleming Outeiro
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EnglishNeuronal disorders such as Parkinson's disease, multiple system atrophy and dementia with Lewy bodies affect millions of patients worldwide. They belong to a group of neurodegenerative diseases called synucleinopathies, which are characterized by the accumulation of abnormally folded α-synuclein (αS) protein in the central and peripheral nervous system. Currently, no disease-modifying therapies are available. Chemical peptide synthesis combined with ligation strategies allows peptides and proteins to be generated in a defined manner, thereby facilitating the study of folding and misfolding processes of different strands. In this thesis, αS peptide fragments are synthesized based on a function-oriented design and ligated with native chemical ligation, bis(2-sulfanylethyl)amino ligation and ketoacid-hydroxylamine ligation. Using spectroscopic techniques like circular dichroism and thioflavin-T fluorescence assay, the structural behavior of αS' native fragments was investigated. In a second project, αS peptide mimics were synthesized with different site-selective glycations, as this common post-translational modification can also influence the aggregation behavior of the protein. Understanding the mechanisms behind the aggregation of αS using chemically designed peptides and proteins will help to develop new therapies for neurological disorders.
Keywords: alpha-synuclein; neurodegenerative diseases; Parkinson´s disease; solid-phase peptide synthesis; ligation methods; post-translational modifications