Neuronal signaling modulates protein homeostasis in <i>Caenorhabditis elegans</i> post-synaptic muscle cells

Garcia, Susana M. D. A.; Casanueva, M. Olivia; Silva, M. Catarina; Amaral, Margarida D.; Morimoto, Richard I.

doi:10.1101/gad.1575307

Cited by 103 publications

(140 citation statements)

References 51 publications

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“…Significantly, we observed a nonautonomous influence of ddlc1 on autophagy in muscle, and this was associated with decreased neuromuscular junction synapse numbers. These data are consistent with the nonautonomous influence of neuronal function on muscle physiology in a Caenorhabditis elegans model of polyglutamine disease (43). In addition, these data are in accordance with the recent demonstration that autophagy in motor neurons regulates synapse development via clearance of Highwire in flies (44).…”

Section: Resultssupporting

confidence: 81%

Dynein light chain 1 is required for autophagy, protein clearance, and cell death inDrosophila

Batlevi

Martin

Pandey

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Autophagy is a catabolic pathway that is important for turnover of long-lived proteins and organelles, and has been implicated in cell survival, tumor progression, protection from infection, neurodegeneration, and cell death. Autophagy and caspases are required for type II autophagic cell death of Drosophila larval salivary glands during development, but the mechanisms that regulate these degradation pathways are not understood. We conducted a forward genetic screen for genes that are required for salivary gland cell death, and here we describe the identification of Drosophila dynein light chain 1 (ddlc1) as a gene that is required for type II cell death. Autophagy is attenuated in ddlc1 mutants, but caspases are active in these cells. ddlc1 mutant salivary glands develop large fibrillar protein inclusions that stain positive for amyloid-specific dyes and ubiquitin. Ectopic expression of Atg1 is sufficient to induce autophagy, clear protein inclusions, and rescue degradation of ddlc1 mutant salivary glands. Furthermore, ddlc1 mutant larvae have decreased motility, and mutations in ddlc1 enhance the impairment of motility that is observed in a Drosophila model of neurodegenerative disease. Significantly, this decrease in larval motility is associated with decreased clearance of protein with polyglutamine expansion, the accumulation of p62 in neurons and muscles, and fewer synaptic boutons. These results indicate that DDLC1 is required for protein clearance by autophagy that is associated with autophagic cell death and neurodegeneration.macroautophagy | protein degradation | neurodegeneration M acroautophagy (autophagy) is a conserved catabolic pathway (1). Autophagy involves the formation of autophagosomes around cytoplasmic components, and fusion with lysosomes enables degradation of autophagosome cargo. Studies of yeast identified Atg genes that are required for autophagy during starvation (2-4). Autophagy is also activated during starvation in animals (5), but the complexity of higher animals, and the association of autophagy with diseases and cell death, raises questions about how autophagy is regulated and cargo is recruited and delivered to lysosomes in multicellular organisms.The role of autophagy in programmed cell death has been a subject of debate (6). Autophagy has a well established role in cell survival, and decreased Atg gene function can promote cell death (7). There is also evidence that autophagy plays a protective role against neurodegeneration in the setting of disease (8, 9), as well as under basal conditions (10, 11). Autophagosomes have been associated with dying cells during development (12, 13), and recent studies indicate that autophagy can promote the degradation and clearance of cells during cell death (14-17). This apparent paradoxical role of autophagy in both cell survival and death raises questions about how autophagy is regulated and influences different cell fates.Drosophila larval salivary glands possess type II cell death morphology during development, and contain numerous autop...

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Section: Resultssupporting

confidence: 81%

Dynein light chain 1 is required for autophagy, protein clearance, and cell death inDrosophila

Batlevi

Martin

Pandey

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…In particular, picrotoxin could cause an imbalance in protein homeostasis in postsynaptic muscle cells through its effect as a GABA A R blocker, consistent with a study by Garcia et al (2007) which stated that modifications that alter the balance of ACh and GABA at the neuromuscular junction (NMJ) cause an increase in polyQ aggregation on C. elegans strains expressing chimeric polyQ fusion proteins to yellow fluorescent protein (YFP).…”

Section: Discussionsupporting

confidence: 55%

“…Additionally, several reports have shown that UNC-49 inactivation provokes an imbalance between ACh and GABA in favor of ACh, causing a defective protein folding and aggregation and therefore inducing a protein homeostasis breakdown in postsynaptic muscle cells (Garcia et al 2007;Gidalevitz et al 2011;Prahlad and Morimoto 2009), which triggers a heat shock response, including a transcription rapid of hsp genes dependent on HSF-1. For this to happen, the misfolding protein accumulation could interact with a complex of monomeric HSF-1 and HSPs to induce its cleavage.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of GABAA receptor is related to heat shock stress response in organism model Caenorhabditis elegans

Camargo

Elizalde

Trujillo

et al. 2016

Cell Stress and Chaperones

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The mechanisms underlying oxidative stress (OS) resistance are not completely clear. Caenorhabditis elegans (C. elegans) is a good organism model to study OS because it displays stress responses similar to those in mammals. Among these mechanisms, the insulin/IGF-1 signaling (IIS) pathway is thought to affect GABAergic neurotransmission. The aim of this study was to determine the influence of heat shock stress (HS) on GABAergic activity in C. elegans. For this purpose, we tested the effect of exposure to picrotoxin (PTX), gammaaminobutyric acid (GABA), hydrogen peroxide, and HS on the occurrence of a shrinking response (SR) after nose touch stimulus in N2 (WT) worms. Moreover, the effect of HS on the expression of UNC-49 (GABA A receptor ortholog) in the EG1653 strain and the effect of GABA and PTX exposure on HSP-16.2 expression in the TJ375 strain were analyzed. PTX 1 mM-or H 2 O 2 0.7 mM-exposed worms displayed a SR in about 80 % of trials. GABA exposure did not cause a SR. HS prompted the occurrence of a SR as did PTX 1 mM or H 2 O 2 0.7 mM exposure. In addition, HS increased UNC-49 expression, and PTX augmented HSP-16.2 expression. Thus, the results of the present study suggest that oxidative stress, through either H 2 O 2 exposure or application of heat shock, inactivates the GABAergic system, which subsequently would affect the oxidative stress response, perhaps by enhancing the activity of transcription factors DAF-16 and HSF-1, both regulated by the IIS pathway and related to hsp-16.2 expression.

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“…These findings therefore indicate that traditional neurotransmitters such as ACh, GABA, or neuropeptides are also not involved in the UNC-18 function. The normal VenusTUNC-6 localization observed in the unc-25 mutant indicated that the muscle homeostasis regulated by GABA (Garcia et al 2007) is not involved in the UNC-18 function. It is also unlikely that the abnormal VenusTUNC-6 localization in unc-18 resulted from the severe defect in muscle contraction observed in this mutant, since the unc-13 mutant, which also displayed a paralyzed phenotype, showed normal localization of VenusTUNC-6.…”

Section: Discussionmentioning

confidence: 94%

Genes Required for Cellular UNC-6/Netrin Localization in Caenorhabditis elegans

et al. 2010

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UNC-6/Netrin is an evolutionarily conserved, secretory axon guidance molecule. In Caenorhabditis elegans, UNC-6 provides positional information to the axons of developing neurons, probably by establishing a concentration gradient from the ventral to the dorsal side of the animal. Although the proper localization of UNC-6 is important for accurate neuronal network formation, little is known about how its localization is regulated. Here, to examine the localization mechanism for UNC-6, we generated C. elegans expressing UNC-6 tagged with the fluorescent protein Venus and identified 13 genes, which are involved in the cellular localization of VenusTUNC-6. For example, in unc-51, unc-14, and unc-104 mutants, the neurons showed an abnormal accumulation of VenusTUNC-6 in the cell body and less than normal level of VenusTUNC-6 in the axon. An aberrant accumulation of VenusTUNC-6 in muscle cells was seen in unc-18 and unc-68 mutants. unc-51, unc-14, and unc-104 mutants also showed defects in the guidance of dorso-ventral axons, suggesting that the abnormal localization of UNC-6 disturbed the positional information it provides. We propose that these genes regulate the process of UNC-6 secretion: expression, maturation, sorting, transport, or exocytosis. Our findings provide novel insight into the localization mechanism of the axon guidance molecule UNC-6/ Netrin.

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Neuronal signaling modulates protein homeostasis in Caenorhabditis elegans post-synaptic muscle cells

Cited by 103 publications

References 51 publications

Dynein light chain 1 is required for autophagy, protein clearance, and cell death inDrosophila

Dynein light chain 1 is required for autophagy, protein clearance, and cell death inDrosophila

Inactivation of GABAA receptor is related to heat shock stress response in organism model Caenorhabditis elegans

Genes Required for Cellular UNC-6/Netrin Localization in Caenorhabditis elegans

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