Selective degeneration of dopaminergic neurons by MPP+ and its rescue by D2 autoreceptors in Drosophila primary culture

Authors

  • Lyle Wiemerslage,

    1. Neuroscience Program, Department of Biological Sciences, Ohio University, Athens, Ohio, USA
    Search for more papers by this author
    • These authors contributed equally to this study.
  • Bradley J. Schultz,

    1. Neuroscience Program, Department of Biological Sciences, Ohio University, Athens, Ohio, USA
    Search for more papers by this author
    • These authors contributed equally to this study.
  • Archan Ganguly,

    1. Neuroscience Program, Department of Biological Sciences, Ohio University, Athens, Ohio, USA
    Current affiliation:
    1. Department of Pathology, 9500 Gilman Drive, UC San Diego, La Jolla, CA, USA
    Search for more papers by this author
  • Daewoo Lee

    Corresponding author
    • Neuroscience Program, Department of Biological Sciences, Ohio University, Athens, Ohio, USA
    Search for more papers by this author

Address correspondence and reprint requests to Daewoo Lee, 213 Life Science Building, Department of Biological Sciences, Ohio University, Athens, OH 45701, USA. E-mail: Leed1@ohio.edu

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.

Ancillary