Development and evaluation of a novel model for synucleinopathy

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.2013-11-2