| Summary: | The loss of dopaminergic neurons is a hallmark of Parkinson’s disease, the aetiology of which is thought to encompass increased levels of oxidative stress and protein misfolding. We used <i>C. elegans</i> to screen for genes that protect dopaminergic neurons from oxidative stress inflicted by 6-hydroxydopamine (6-OHDA) uptake and isolated the neuroligin-like gene <i>glit-1</i> and the transthyretin-related gene <i>ttr-33</i>. Neuroligins are transmembrane proteins involved in the development and function of synapses. We provide evidence that <i>glit-1</i> and the previously identified tetraspanin <i>tsp-17</i> are associated with the regulation of dopamine turnover, impacting on 6-OHDA uptake into the neurons: <i>glit-1</i> and <i>tsp-17</i> mutant sensitivities to 6-OHDA are not additive and both mutants exhibit signs of increased dopamine signalling. A P<i>glit-1</i>::GFP transcriptional reporter is expressed in the pharynx, intestine and possibly dopaminergic neurons. The second isolated mutant <i>ttr-33</i> in contrast does not display dopamine-related behavioural defects. TTR-33 is likely secreted from the posterior arcade cells in the head and might play a role in cell engulfment, similar to another member of the <i>C. elegans</i> transthyretin-related protein family. <i>C. elegans</i> dopaminergic neurons seem to be phagocytosed after 6-OHDA intoxication as mutations in the engulfment pathway largely suppress neuronal loss. Before being engulfed, dopaminergic neurons likely undergo a necrosis-like cell death − since mutations in apoptosis pathway genes do not prevent, but rather increase neurodegeneration. In addition, the mutated TTR-33 protein might be more prone to aggregation, similar to its human orthologue transthyretin which is associated with amyloid diseases. Indeed, inhibition of the <i>C. elegans</i> unfolded protein response partly alleviates dopaminergic neurodegeneration in the <i>ttr-33</i> mutant. On the organismal level,<i> glit1</i>, <i>tsp-17</i> and <i>ttr-33</i> mutations cause oxidative stress sensitivity but resistance to protein folding stress. In summary, we think that <i>tsp-17</i>, <i>glit-1</i> and <i>ttr-33</i> play a role in the organismal defence against environmental stress.
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