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Keywords:

  • D2 agonist;
  • DD2R;
  • Drosophila melanogaster ;
  • Parkinson's disease;
  • primary neuronal culture

Abstract

Drosophila melanogaster is widely used to study genetic factors causing Parkinson's disease (PD) largely because of the use of sophisticated genetic approaches and the presence of a high conservation of gene sequence/function between Drosophila and mammals. However, in Drosophila, little has been done to study the environmental factors which cause over 90% of PD cases. We used Drosophila primary neuronal culture to study degenerative effects of a well-known PD toxin MPP+. Dopaminergic (DA) neurons were selectively degenerated by MPP+, whereas cholinergic and GABAergic neurons were not affected. This DA neuronal loss was because of post-mitotic degeneration, not by inhibition of DA neuronal differentiation. We also found that MPP+-mediated neurodegeneration was rescued by D2 agonists quinpirole and bromocriptine. This rescue was through activation of Drosophila D2 receptor DD2R, as D2 agonists failed to rescue MPP+-toxicity in neuronal cultures prepared from both a DD2R deficiency line and a transgenic line pan-neuronally expressing DD2R RNAi. Furthermore, DD2R autoreceptors in DA neurons played a critical role in the rescue. When DD2R RNAi was expressed only in DA neurons, MPP+ toxicity was not rescued by D2 agonists. Our study also showed that rescue of DA neurodegeneration by Drosophila DD2R activation was mediated through suppression of action potentials in DA neurons.