Stabilität der Synuklein Proteine
Stability of Synuclein Proteins
by Diana Voll
Date of Examination:2025-02-04
Date of issue:2025-01-22
Advisor:Prof. Dr. Mathias Bähr
Referee:Prof. Dr. Mathias Bähr
Referee:Prof. Dr. Markus Zweckstetter
Referee:Prof. Dr. Ralf Dressler
Sponsor:Vorsprung Promotionskolleg der Klinik für Neurologie der Universitätsmedizin Göttingen
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Abstract
English
The protein α-synuclein, which belongs to the synuclein family along with β- and γ-synuclein, plays a crucial role in the pathogenesis of Parkinson's disease. β-synuclein is also etiopathologically linked to the development of a synucleinopathy, dementia with Lewy bodies (DLB), due to two mutations. In contrast, γ-synuclein is not associated with neurodegenerative diseases and only shows the ability to form insoluble aggregates under specific experimental conditions. The aggregation potential of the three proteins, leading to the formation of toxic species, is determined by various factors, with protein concentration playing a decisive role. This concentration can be influenced by factors such as overexpression in experimental contexts or duplications and triplications of the SNCA gene in early-onset Parkinson's disease (PD). Besides the regulation of synthesis, protein balance is maintained by degradation mechanisms. Differences in degradation and thus protein stability have been suggested as reasons for the varying aggregation potentials and neurotoxicities of the three synuclein proteins. In the present study, the degradation kinetics of the three proteins were examined using a cell culture model in embryonic rat cortex neurons with transgenic overexpression of the three synucleins through adeno-associated viral vectors. The three synuclein proteins exhibited very similar degradation kinetics, characterized by exponential decay. Initially, a rapid degradation was observed, with a reduction in protein concentration by 70% during the first seven days after expression cessation, followed by a slower degradation phase in which protein concentration approached zero over the next seven days. Based on these findings, the three synuclein proteins appear to share similar degradation kinetics. Differences in protein stability do not seem to be a decisive factor in the varying neurotoxicities of α-, β-, and γ-synuclein
Keywords: Synucleinopathy; Alpha-Synuclein; Beta-Synuclein; Gamma-Synuclein; Synuclein; Protein Degradation; Parkinson's Disease