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6-OHDA-induced dopaminergic neurodegeneration in Caenorhabditis elegans is promoted by the engulfment pathway and inhibited by the transthyretin-related protein TTR-33.

ABSTRACT: Oxidative stress is linked to many pathological conditions including the loss of dopaminergic neurons in Parkinson's disease. The vast majority of disease cases appear to be caused by a combination of genetic mutations and environmental factors. We screened for genes protecting Caenorhabditis elegans dopaminergic neurons from oxidative stress induced by the neurotoxin 6-hydroxydopamine (6-OHDA) and identified the transthyretin-related gene ttr-33. The only described C. elegans transthyretin-related protein to date, TTR-52, has been shown to mediate corpse engulfment as well as axon repair. We demonstrate that TTR-52 and TTR-33 have distinct roles. TTR-33 is likely produced in the posterior arcade cells in the head of C. elegans larvae and is predicted to be a secreted protein. TTR-33 protects C. elegans from oxidative stress induced by paraquat or H2O2 at an organismal level. The increased oxidative stress sensitivity of ttr-33 mutants is alleviated by mutations affecting the KGB-1 MAPK kinase pathway, whereas it is enhanced by mutation of the JNK-1 MAPK kinase. Finally, we provide genetic evidence that the C. elegans cell corpse engulfment pathway is required for the degeneration of dopaminergic neurons after exposure to 6-OHDA. In summary, we describe a new neuroprotective mechanism and demonstrate that TTR-33 normally functions to protect dopaminergic neurons from oxidative stress-induced degeneration, potentially by acting as a secreted sensor or scavenger of oxidative stress.

SUBMITTER: Offenburger SL

PROVIDER: S-EPMC5773127 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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6-OHDA-induced dopaminergic neurodegeneration in Caenorhabditis elegans is promoted by the engulfment pathway and inhibited by the transthyretin-related protein TTR-33.

Offenburger Sarah-Lena SL Ho Xue Yan XY Tachie-Menson Theresa T Coakley Sean S Hilliard Massimo A MA Gartner Anton A

PLoS genetics 20180118 1

Oxidative stress is linked to many pathological conditions including the loss of dopaminergic neurons in Parkinson's disease. The vast majority of disease cases appear to be caused by a combination of genetic mutations and environmental factors. We screened for genes protecting Caenorhabditis elegans dopaminergic neurons from oxidative stress induced by the neurotoxin 6-hydroxydopamine (6-OHDA) and identified the transthyretin-related gene ttr-33. The only described C. elegans transthyretin-rela ...[more]

PMID: 29346382

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Project description: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.

Project description:BackgroundTTR (transthyretin) cardiac amyloidosis is caused by dissociation of TTR into monomers, which misassemble into amyloid fibrils. TTR stabilizers act at the dimer-dimer interface to prevent dissociation. We investigated differences in survival among patients with TTR cardiac amyloidosis on stabilizer medications compared with those not on stabilizers.Methods and resultsA retrospective study of patients with TTR cardiac amyloidosis presenting to a single center was conducted. Baseline characteristics were compared between those treated with stabilizers and those not treated with stabilizers. Cox proportional hazards modeling assessed for univariate predictors of the composite outcome of death or orthotopic heart transplant (OHT). Multivariable Cox proportional hazards assessed whether stabilizer treatment was independently associated with improved death or OHT after controlling for significant univariate predictors. One hundred twenty patients (mean age, 75±8, 88% male) were included: 29 patients who received stabilizers and 91 patients who did not. Stabilizer use was associated with a lower risk of the combined end point of death or OHT (hazard ratio, 0.32; 95% confidence interval, 0.18-0.58; P<0.0001). Subjects treated with stabilizers were more likely to be of White race (93% versus 55%; P<0.001), classified as New York Heart Association classes I and II (79% versus 38%; P=0.002), less likely to have a mutation (10% versus 36%; P=0.010), have lower troponin I (median 0.06 versus 0.12 ng/mL; P=0.002), and higher left ventricular ejection fraction (49% versus 40%; P=0.011), suggesting earlier stage of disease. In multivariable Cox analysis, the association between stabilizer and death or OHT persisted when adjusted for all noncollinear univariate predictors with P<0.05 (hazard ratio, 0.37; 95% confidence interval, 0.19-0.75; P=0.003).ConclusionsTTR stabilizers are associated with decreased death and OHT in TTR cardiac amyloidosis. These results need to be confirmed by ongoing randomized clinical trials.

Dataset Information

6-OHDA-induced dopaminergic neurodegeneration in Caenorhabditis elegans is promoted by the engulfment pathway and inhibited by the transthyretin-related protein TTR-33.

Publications

6-OHDA-induced dopaminergic neurodegeneration in Caenorhabditis elegans is promoted by the engulfment pathway and inhibited by the transthyretin-related protein TTR-33.

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