Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer disease. It is characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Dopaminergic signalling deregulation leads to resting tremor and postural instability. Genetic factors as well as environmental stress such as the use of the pesticide paraquat, have been shown to trigger PD. Although several key molecular players have been identified and characterized in PD models, little is known about the cellular glial mechanisms that may regulate the survival versus death of dopaminergic neurons.
To identify glial genes involved in dopaminergic neuronal cell death, we combined a candidate gene approach in Drosophila melanogaster and a transcriptomic analysis on the substantia nigra from PD patients. Among the Drosophila candidate genes, 20 were found to have homologous genes in human that were differentially expressed in PD. And among these 20 genes, we identified split-ends (spen) has being protector in a chemical model of Parkinson induced by paraquat treatment in Drosophila. Spen belongs with spenito to the evolutionary conserved SPEN proteins family. Spen is implicated in multiple cellular processes such as neuronal and glial cell fate or axon guidance during nervous system development and we have recently shown that spen was necessary for interomatidial cells (IOCs) survival during retina development.
We found that brain expression of spen is modulated by paraquat treatment and that flies heterozygous for a loss of function mutation in spen exhibit an enhanced vulnerability to paraquat, which indicates a prosurvival function of spen. Importantly, specific depletion of spen in glial cells also renders flies more sensitive to paraquat, while, reversely, over-expression of spen in glial cells has a protective effect. In support of previous reports, a bio-informatics large scale analysis of transcriptomic data indicates that spen and the Notch pathway are tightly interconnected. Using a Notch reporter construct, we indeed demonstrate that spen is required for Notch activity in glial cells. Furthermore, modulation of Notch in glial cells is associated with higher sensitivity to paraquat treatment.
Together, these results suggest that in pharmacological models of PD, spen expression in glial cells is required for a Notch-dependent mechanism of neuronal resistance to oxidative stress. . This finding further supports the importance of glia-mediated neuroprotective pathways under neurodegenerative conditions.