Progressive Degeneration of Dopaminergic Neurons through TRP Channel-Induced Cell Death

Nagarajan, Archana; Ye, Ning; Reisner, Kaja; Buraei, Zafir; Larsen, Jan Petter; Hobert, Oliver; Doitsidou, Maria

doi:10.1523/jneurosci.4540-13.2014

Cited by 29 publications

(33 citation statements)

References 62 publications

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“…Given that DA signaling promotes the expression of xenobiotic stress response genes, we reasoned that such signaling might be (i) activated by pathogenic bacteria and (ii) required for animals to survive pathogenic infection. To determine whether the dopaminergic neurons specifically are required to promote Ub G76V -GFP turnover in epithelia, we took advantage of a transgene, P dat-1 ::trp-4(d), that expresses a toxic TRP-4 mutant channel under the control of the dat-1 promoter and is thus only active in dopaminergic neurons (Nagarajan et al, 2014). We found that Ub G76V -GFP turnover is reduced in mec-5 and trp-4 mutants (Figs 4A and EV3D), although not to the same extent as in DA signaling mutants, indicating that the activation of these neurons by environmental mechanical stimulation is required to fully promote Ub G76V -GFP turnover in epithelia, but that these dopaminergic neurons might also promote Ub G76V -GFP turnover in response to additional environmental cues besides mechanical stimulation.…”

Section: Mechanosensory Dopaminergic Neurons Are Required To Modulatementioning

confidence: 99%

“…TRP-4 is expressed primarily in dopaminergic neurons (ADE, CEP, PDE), but it is also found in the neurons DVA and DVC. To determine whether the dopaminergic neurons specifically are required to promote Ub G76V -GFP turnover in epithelia, we took advantage of a transgene, P dat-1 ::trp-4(d), that expresses a toxic TRP-4 mutant channel under the control of the dat-1 promoter and is thus only active in dopaminergic neurons (Nagarajan et al, 2014). The transgene triggers a progressive cell death of the dopaminergic neurons but not DVA or DVC.…”

Section: Mechanosensory Dopaminergic Neurons Are Required To Modulatementioning

confidence: 99%

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Dopamine signaling promotes the xenobiotic stress response and protein homeostasis

2016

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Multicellular organisms encounter environmental conditions that adversely affect protein homeostasis (proteostasis), including extreme temperatures, toxins, and pathogens. It is unclear how they use sensory signaling to detect adverse conditions and then activate stress response pathways so as to offset potential damage. Here, we show that dopaminergic mechanosensory neurons in C. elegans release the neurohormone dopamine to promote proteostasis in epithelia. Signaling through the DA receptor DOP-1 activates the expression of xenobiotic stress response genes involved in pathogenic resistance and toxin removal, and these genes are required for the removal of unstable proteins in epithelia. Exposure to a bacterial pathogen (Pseudomonas aeruginosa) results in elevated removal of unstable proteins in epithelia, and this enhancement requires DA signaling. In the absence of DA signaling, nematodes show increased sensitivity to pathogenic bacteria and heat-shock stress. Our results suggest that dopaminergic sensory neurons, in addition to slowing down locomotion upon sensing a potential bacterial feeding source, also signal to frontline epithelia to activate the xenobiotic stress response so as to maintain proteostasis and prepare for possible infection.

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Section: Mechanosensory Dopaminergic Neurons Are Required To Modulatementioning

confidence: 99%

Section: Mechanosensory Dopaminergic Neurons Are Required To Modulatementioning

confidence: 99%

Dopamine signaling promotes the xenobiotic stress response and protein homeostasis

2016

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“…Although several studies have examined axonal degeneration in C. elegans in the context of neurodegenerative disease models and neuronal dysfunction (Calixto et al, 2012; Nagarajan et al, 2014; Neumann and Hilliard, 2014; Neumann et al, 2011), no Wallerian degeneration (i.e. severed axon) paradigm has been investigated.…”

Section: Introductionmentioning

confidence: 99%

The Apoptotic Engulfment Machinery Regulates Axonal Degeneration in C. elegans Neurons

et al. 2016

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Axonal degeneration is a characteristic feature of neurodegenerative disease and nerve injury. Here, we characterize axonal degeneration in Caenorhabditis elegans neurons following laser-induced axotomy. We show that this process proceeds independently of the WLDS and Nmnat pathway, and requires the axonal clearance machinery that includes the conserved transmembrane receptor CED-1/Draper, the adaptor protein CED-6, the guanine nucleotide exchange factor complex Crk/Mbc/dCed-12 (CED-2/CED-5/CED-12) and the small GTPase Rac1 (CED-10). We demonstrate that CED-1 and CED-6 function non-cell-autonomously in the surrounding hypodermis, which we show acts as the engulfing tissue for the severed axon. Moreover, we establish a function in this process for CED-7, an ATP-binding cassette (ABC) transporter, and NRF-5, a lipid-binding protein, both associated with release of lipid-vesicles during apoptotic cell clearance. Thus, our results reveal the existence of a WLDS /Nmnat-independent axonal degeneration pathway, conservation of the axonal clearance machinery, and a function for CED-7 and NRF-5 in this process.

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“…Since dopaminergic neurons do not undergo apoptosis after 6-OHDA exposure, we aimed to determine if they die via a necrosis-like cell death. Mutation of the C. elegans calreticulin CRT-1, a calcium-binding and calcium-storing chaperone in the endoplasmic reticulum, prevents several necrosis-type cell deaths [39,40]. In contrast, we found that crt-1 mutation led to a highly increased loss of dopaminergic neurons after exposure to 6-OHDA in an otherwise wild-type background (Fig 8A-C).…”

Section: Resultsmentioning

confidence: 81%

Mutations inC. elegansneuroligin-likeglit-1, the apoptosis pathway and the calcium chaperonecrt-1increase dopaminergic neurodegeneration after 6-OHDA treatment

Offenburger

Jongsma

Gartner

2017

Preprint

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Mutations in C. elegans neuroligin-like glit-1, the apoptosis pathway and the 1 calcium chaperone crt-1 increase dopaminergic neurodegeneration after 6-2 Abstract 9The loss of dopaminergic neurons is a hallmark of Parkinson's disease, the aetiology of which is 10 associated with increased levels of oxidative stress. We used C. elegans to screen for genes that 11 protect dopaminergic neurons against oxidative stress and isolated glit-1 (gliotactin (Drosophila 12 neuroligin-like) homologue). Loss of the C. elegans neuroligin-like glit-1 causes increased 13 dopaminergic neurodegeneration after treatment with 6-hydroxydopamine (6-OHDA), an oxidative-14 stress inducing drug that is specifically taken up into dopaminergic neurons. Furthermore, glit-1 15 mutants exhibit increased sensitivity to oxidative stress induced by H 2 O 2 and paraquat. We provide 16 evidence that GLIT-1 acts in the same genetic pathway as the previously identified tetraspanin TSP-17 17. After exposure to 6-OHDA and paraquat, glit-1 and tsp-17 mutants show almost identical, non-18 additive hypersensitivity phenotypes and exhibit highly increased induction of oxidative stress 19 reporters. TSP-17 and GLIT-1 are both expressed in dopaminergic neurons. In addition, the 20 neuroligin-like GLIT-1 is expressed in pharynx, intestine and several unidentified cells in the head. 21GLIT-1 is homologous, but not orthologous to neuroligins, transmembrane proteins required for the 22 function of synapses. The Drosophila GLIT-1 homologue Gliotactin in contrast is required for 23 epithelial junction formation. We report that GLIT-1 likely acts in multiple tissues to protect against 24 6-OHDA, and that the epithelial barrier of C. elegans glit-1 mutants does not appear to be 25 compromised. We further describe that hyperactivation of the SKN-1 oxidative stress response 26 pathway alleviates 6-OHDA-induced neurodegeneration. In addition, we find that mutations in the 27 canonical apoptosis pathway and the calcium chaperone crt-1 cause increased 6-OHDA-induced 28 dopaminergic neuron loss. In summary, we report that the neuroligin-like GLIT-1, the canonical 29 apoptosis pathway and the calreticulin CRT-1 are required to prevent 6-OHDA-induced dopaminergic 30 neurodegeneration. 31 Author summary 32Neurons use dopamine as a chemical messenger to mediate diverse behaviours. The gradual loss of 33 dopaminergic neurons in specific brain areas is a hallmark of Parkinson's disease. The increased 34 occurrence of highly reactive oxygen radicals, also called oxidative stress, is assumed to contribute 35 to the demise of dopaminergic neurons. In this study we searched for genes that protect 36 dopaminergic neurons against oxidative stress. We used the nematode C. elegans, a well-37 characterised model organism whose dopamine signalling system is very similar to that of humans. 38When C. elegans is exposed to 6-hydroxydopamine, an oxidative stress-inducing compound, 39 dopaminergic neurons gradually die. Our major findings include: (i) absence of the neuroligin-like 40 gene gl...

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Progressive Degeneration of Dopaminergic Neurons through TRP Channel-Induced Cell Death

Cited by 29 publications

References 62 publications

Dopamine signaling promotes the xenobiotic stress response and protein homeostasis

Dopamine signaling promotes the xenobiotic stress response and protein homeostasis

The Apoptotic Engulfment Machinery Regulates Axonal Degeneration in C. elegans Neurons

Mutations inC. elegansneuroligin-likeglit-1, the apoptosis pathway and the calcium chaperonecrt-1increase dopaminergic neurodegeneration after 6-OHDA treatment

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