AbstractThe 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 C. elegans to screen for genes that protect dopaminergic neurons from oxidative stress inflicted by 6-hydroxydopamine (6-OHDA) uptake and isolated the neuroligin-like gene glit-1 and the transthyretin-related gene ttr-33. Neuroligins are transmembrane proteins involved in the development and function of synapses. We provide evidence that glit-1 and the previously identified tetraspanin tsp-17 are associated with the regulation of dopamine turnover, impacting on 6-OHDA uptake into the neurons: glit-1 and tsp-17 mutant sensitivities to 6-OHDA are not additive and both mutants exhibit signs of increased dopamine signalling. A Pglit-1::GFP transcriptional reporter is expressed in the pharynx, intestine and possibly dopaminergic neurons. The second isolated mutant ttr-33 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 C. elegans transthyretin-related protein family. C. elegans 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 C. elegans unfolded protein response partly alleviates dopaminergic neurodegeneration in the ttr-33 mutant. On the organismal level, glit1, tsp-17 and ttr-33 mutations cause oxidative stress sensitivity but resistance to protein folding stress. In summary, we think that tsp-17, glit-1 and ttr-33 play a role in the organismal defence against environmental stress.
|Date of Award||2016|
|Sponsors||Wellcome Trust & Parkinson’s UK|
|Supervisor||Anton Gartner (Supervisor)|
A transthyretin-related gene and a neuroligin-like gene prevent 6-hydroxydopamine-induced dopaminergic neurodegeneration in C. elegans
Offenburger, S. (Author). 2016
Student thesis: Doctoral Thesis › Doctor of Philosophy