Entwicklung und Evaluation eines neuen Modells für Synucleinopathien

Development and evaluation of a novel model for synucleinopathy

by Marlena Schnieder
Doctoral thesis
Date of Examination:2013-11-19
Date of issue:2013-11-19
Advisor:Prof. Dr. Pawel Kermer
Referee:Prof. Dr. Pawel Kermer
Referee:Prof. Dr. Michael Thumm
Persistent Address: http://dx.doi.org/10.53846/goediss-4154

 

 

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Abstract

English

Missfolding and oligomerization of alpha-synuclein is considered a central event in different neurodegenerative diseases like Parkinson’s disease and related disorders. As the function of alpha-synuclein is still a matter of intense research, testing for therapeutic and neuroprotective strategies relies on assessment of alpha-synuclein induced cell death and alterations in pathways involving cellular homeostasis known to be altered in synucleinopathy. To complicate the matter, even forced overexpression of alpha-synuclein in cell lines, which represent the easiest tool to screen for treatment regimens, does not induce a relevant toxicity. We generated alpha-synuclein repeat constructs fused by flexible protein linkers, which allow the oligomerization of alpha-synuclein due to spatial proximity. Overexpression of these constructs in equimolar ratio to alpha-synuclein monomers induce aggregation and exhibit a markedly increased toxicity in SH-SY5Y cells and primary hippocampal neurons. Furthermore, the alpha-synuclein repeat constructs induced proteasomal dysfunction and as well an impairment of the macroautophagy.Therefore this novel model system for synucleinopathy imitates pathophysiological alterations and offers a valuable tool to study synucleinopathy in living cells and to screen for potential treatments for Parkinson’s disease.
Keywords: alpha-Synuclein; aggregation; autophagy; proteasomal dysfunction
 
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