Mutations inC. elegansneuroligin-likeglit-1, the apoptosis pathway and the calcium chaperonecrt-1increase dopaminergic neurodegeneration after 6-OHDA treatment
Authors: Offenburger Sarah-Lena , Jongsma Elisabeth , Gartner Anton 
Published: October 2017

AbstractThe loss of dopaminergic neurons is a hallmark of Parkinson’s disease, the aetiology of which is associated with increased levels of oxidative stress. We usedC. elegansto screen for genes that protect dopaminergic neurons against oxidative stress and isolatedglit-1 (gliotactin (Drosophila neuroligin-like) homologue). Loss of theC. elegansneuroligin-likeglit-1causes increased dopaminergic neurodegeneration after treatment with 6-hydroxydopamine (6-OHDA), an oxidative- stress inducing drug that is specifically taken up into dopaminergic neurons. Furthermore,glit-1mutants exhibit increased sensitivity to oxidative stress induced by H2O2and paraquat. We provide evidence that GLIT-1 acts in the same genetic pathway as the previously identifiedtetraspanin TSP-17. After exposure to 6-OHDA and paraquat,glit-1andtsp-17mutants show almost identical, non-additive hypersensitivity phenotypes and exhibit highly increased induction of oxidative stress reporters. TSP-17 and GLIT-1 are both expressed in dopaminergic neurons. In addition, the neuroligin-like GLIT-1 is expressed in pharynx, intestine and several unidentified cells in the head. GLIT-1 is homologous, but not orthologous to neuroligins, transmembrane proteins required for the function of synapses. TheDrosophilaGLIT-1 homologue Gliotactin in contrast is required for epithelial junction formation. We report that GLIT-1 likely acts in multiple tissues to protect against 6-OHDA, and that the epithelial barrier ofC. elegans glit-1mutants does not appear to be compromised. We further describe that hyperactivation of the SKN-1 oxidative stress response pathway alleviates 6-OHDA-induced neurodegeneration. In addition, we find that mutations in the canonical apoptosis pathway and the calcium chaperonecrt-1cause increased 6-OHDA-induced dopaminergic neuron loss. In summary, we report that the neuroligin-like GLIT-1, the canonical apoptosis pathway and the calreticulin CRT-1 are required to prevent 6-OHDA-induced dopaminergic neurodegeneration.Author summaryNeurons use dopamine as a chemical messenger to mediate diverse behaviours. The gradual loss of dopaminergic neurons in specific brain areas is a hallmark of Parkinson’s disease. The increased occurrence of highly reactive oxygen radicals, also called oxidative stress, is assumed to contribute to the demise of dopaminergic neurons. In this study we searched for genes that protect dopaminergic neurons against oxidative stress. We used the nematodeC. elegans, a well- characterised model organism whose dopamine signalling system is very similar to that of humans. WhenC. elegansis exposed to 6-hydroxydopamine, an oxidative stress-inducing compound, dopaminergic neurons gradually die. Our major findings include: (i) absence of the neuroligin-like geneglit-1causes highly increased cell death of dopaminergic neurons after 6-OHDA exposure; (ii) GLIT-1 acts in a similar manner as the previously identified tetraspanin TSP-17; (iii) GLIT-1 and TSP-17 also protectC. elegansfrom other types of oxidative stress; and (iv) the programmed cell death pathway and a calcium chaperone protect dopaminergic neurons as well. Collectively, this study shows that apoptosis proteins, the calcium chaperone CRT-1 and the neuroligin-like GLIT-1 protect against neurodegeneration after oxidative stress exposure.