Interaktion zwischen Alpha-Synuclein und Dopamintransporter: Untersuchungen an heterologen Expressionsmodellen
Tan, Eva Maria Schiang Uhn
LicenseStandard (Fassung vom 03.05.2003)
There are many known factors for the occurrence of Morbus Parkinson. It has been unknown how they interact. In the present study the influence of human dopamine transporter (hDAT) and alpha-synuclein mutations towards the toxicity of Parkinson-inducing toxins has been examined. Therefore we generated an in vitro Parkinson model. In a former study human embryonic kidney cells have been transfected with hDAT. These have been transfected with alpha-synuclein and its mutations. These cells were incubated with Parkinson-inducing toxins. The overall cell survival was measured with the MTT-assay. We were able to show that all alpha-synuclein isoforms aggravated a systemic mitochondrial-complex-I-inhibition through rotenone. But only the mutant alpha-synuclein were able to induce hDAT-dependant toxicity of very low concentrations of 1-Methyl-4-Phenylpyridinium ion (MPP+) in comparison to wild-type alpha-synuclein. We were able to show that there is hDAT-dependant interaction of mutant alpha-synuclein with Hydroxydopamine (6-OHDA) exposition in all cell lines. The inhibition of proteasomes through lactacystin did not have any influence on the MPP+ mediated toxicity in all cell lines. Put together our results implicate a neurotoxicity that is mediated via interaction of alpha-synuclein and hDAT. Oxidativ stress, alpha-synuclein and hDAT may cause in combination with protofibrill formation a mitochondrial dysfunction and may enhance the pathogenesis of idiopathic Parkinson syndrome. As our present results may show a new pathomechanism for a selective vulnerability of the dopaminergic cells towards 6-OHDA, our result can contribute to a better understanding in the aethiopathogenesis of selective neurodegeneration in idiopathic Parkinson syndrome. It remains unknown if the transport of toxic agents into the cell in the presence of alpha-synuclein isoforms in co-expression of hDAT is responsible for the increased vulnerability of the various neurotoxins.