Disruption of dopamine homeostasis underlies selective neurodegeneration mediated by α‐synuclein

摘要: A key challenge in Parkinson's disease research is to understand mechanisms underlying selective degeneration of dopaminergic neurons mediated by genetic factors such as alpha-synuclein (alpha-Syn). The present study examined whether dopamine (DA)-dependent oxidative stress underlies alpha-Syn-mediated neurodegeneration using Drosophila primary neuronal cultures. Green fluorescent protein (GFP) was used identify live cultures prepared on a marked photoetched coverslip, which allowed us repeatedly access preidentified at different time points non-invasive manner. This tracking GFP-marked revealed age-dependent mutant human alpha-Syn (A30P). Degeneration rescued when were incubated with 1 mm glutathione from Day 3 after culturing. Furthermore, depletion cytoplasmic DA 100 microm alpha-methyl-p-tyrosine completely the early stage cell loss, demonstrating that plays major role stress-dependent alpha-Syn. In contrast, overexpression tyrosine hydroxylase gene (dTH1) alone caused enhanced synthesis cytoplasm. Age-dependent loss comparable vs dTH1-overexpressed cultures, indicating increased levels cytoplasm critical change downstream function. Finally, vesicular monoamine transporter through sequestration into synaptic vesicles, further main cause alpha-Syn-induced disruption homeostasis. All these results demonstrate elevated factor neurodegeneration.