Pharmakologische rho-Kinasen-Inhibition im H4-Zelllinien-Modell des Morbus Parkinson

Pharmacological rho-kinase inhibition in the H4 cell line model of Parkinson's disease

by Hagen Lothar Walle
Doctoral thesis
Date of Examination:2024-04-23
Date of issue:2024-04-26
Advisor:Prof. Dr. Paul Lingor
Referee:Dr. Luis Felipe Opazo Dávila
Referee:Prof. Dr. Ralf Dressel
Persistent Address: http://dx.doi.org/10.53846/goediss-10454

 

 

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Abstract

English

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, unfortunately there are no curative therapeutic approaches to date. Rho-associated protein kinase (ROCK) has been described as a novel neuroprotective target in PD. The aggregation of alpha-synuclein (α-Syn), particularly in oligomeric form, is a key feature in the pathogenesis of PD. In the H4 cell model, human neuroglioma cells were transfected with synT, an alpha-synuclein derivative, and synphillin-1 and subsequently formed aggregate complexes. To evaluate the antiaggregative potential of ROCK inhibition, the cells were treated with fasudil, a molecule already approved for use in humans, and other inhibitors. The results show a decrease of oligomeric synT structures in column chromatography as well as a reduction of aggregate-bearing cells after transfection. An induction of autophagy within the H4 cells by treatment with fasudil can be assumed as the underlying mechanism. Together with the neuroprotective and regenerative properties of fasudil already demonstrated in other studies, this offers a potential causal therapeutic option for the disease.
Keywords: Parkinson's disease; alpha-Synuclein; Fasudil; ROCK; rho-Kinase Inhibition; Synphilin-1; rho-Kinase; synT; aggregation
Schlagwörter: Morbus Parkinson
 
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