RRC ID 51540
Author Offenburger SL, Jongsma E, Gartner A.
Title Mutations in Caenorhabditis elegans neuroligin-like glit-1, the apoptosis pathway and the calcium chaperone crt-1 increase dopaminergic neurodegeneration after 6-OHDA treatment.
Journal PLoS Genet
Abstract 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 (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.
Volume 14(1)
Pages e1007106
Published 2018-1-1
DOI 10.1371/journal.pgen.1007106
PMID 29346364
PMC PMC5773152
MeSH Animals Animals, Genetically Modified Apoptosis / genetics* Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / genetics* Caenorhabditis elegans Proteins / metabolism Calcium Calreticulin / genetics* Calreticulin / metabolism Dopaminergic Neurons / metabolism* Hydrogen Peroxide / pharmacology Membrane Proteins / genetics* Membrane Proteins / metabolism Molecular Chaperones / genetics Molecular Chaperones / metabolism Mutation Nerve Degeneration / chemically induced Nerve Degeneration / genetics* Nerve Degeneration / metabolism Nerve Tissue Proteins / genetics* Nerve Tissue Proteins / metabolism Oxidants / pharmacology Oxidative Stress / drug effects Oxidopamine Paraquat / pharmacology
IF 5.175
Times Cited 7
C.elegans tm1817 tm4995