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

Sarah-Lena Offenburger, Elisabeth Jongsma, Anton Gartner (Lead / Corresponding author)

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    16 Citations (Scopus)
    261 Downloads (Pure)


    The loss of dopaminergic neurons is a hallmark of Parkinsons 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 (gliotactin (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 H2O2 and paraquat. We provide evidence that GLIT-1 acts in the same genetic pathway as the previously identified tetraspanin 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.
    Original languageEnglish
    Article numbere1007106
    Pages (from-to)1-34
    Number of pages34
    JournalPLoS Genetics
    Issue number1
    Publication statusPublished - 18 Jan 2018


    • Animals
    • Animals, Genetically Modified
    • Apoptosis/genetics
    • Caenorhabditis elegans Proteins/genetics
    • Caenorhabditis elegans/genetics
    • Calcium
    • Calreticulin/genetics
    • Dopaminergic Neurons/metabolism
    • Hydrogen Peroxide/pharmacology
    • Membrane Proteins/genetics
    • Molecular Chaperones/genetics
    • Mutation
    • Nerve Degeneration/chemically induced
    • Nerve Tissue Proteins/genetics
    • Oxidants/pharmacology
    • Oxidative Stress/drug effects
    • Oxidopamine
    • Paraquat/pharmacology

    ASJC Scopus subject areas

    • Genetics(clinical)
    • Genetics
    • Ecology, Evolution, Behavior and Systematics
    • Molecular Biology
    • Cancer Research


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