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The loss of dopaminergic neurons is a hallmark of Parkinson’s disease, the aetiology of which is associated with increased levels of oxidative stress. We used  C .  elegans  to screen for genes that protect dopaminergic neurons against oxidative stress and isolated  glit-1  (  gli   o   t   actin (Drosophila neuroligin-like) homologue) . Loss of the  C .  elegans  neuroligin-like  glit-1  causes 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-1  mutants exhibit increased sensitivity to oxidative stress induced by H 2 O 2  and paraquat. We provide evidence that GLIT-1 acts in the same genetic pathway as the previously identified  t etra sp anin TSP-17. After exposure to 6-OHDA and paraquat,  glit-1  and  tsp-17  mutants 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. The  Drosophila  GLIT-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 of  C .  elegans glit-1  mutants 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 chaperone  crt-1  cause 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.

plos genetics

Mutations in Caenorhabditis elegans neuroligin-like glit-1, the apoptosis pathway and the calcium chaperone crt-1 increase dopaminergic neurodegeneration after 6-OHDA treatment