The Vacuolar H+-ATPase Mediates Intracellular Acidification Required for Neurodegeneration in C. elegans

Syntichaki, Popi; Samara, Chrysanthi; Tavernarakis, Nektarios

doi:10.1016/j.cub.2005.05.057

Cited by 99 publications

(101 citation statements)

References 29 publications

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“…vha-12 mutants showed no difference in vulnerability to higher concentrations of MPP + -induced loss of GFP in the dendrites of ADEs and CEPs (see Supplementary information, Figure S2). We did not achieve complete blockage of MPP + -induced dopamine neuron degeneration, which is consistent with the previous report showing that vha-12 deficiency cannot completely block necrosis [9]. One of the core features of necrosis is a gain in cell volume (oncosis), while the main feature of apoptosis is the reduction of cell volume (pyknosis).…”

Section: Dear Editorsupporting

confidence: 91%

“…According to the gene expression patterns, vha-12 and crt-1 are most likely to be involved in dopamine neuron death [8]. It is known that the vacuolar H (+)-ATPase (vha-12), a pump that acidifies lysosomes and other intracellular organelles, is broadly required for necrosis caused by deleterious mutations in a diverse set of genes (mec-4, deg-3) and by hypoxic conditions in C. elegans [9]. Lossof-function mutation in crt-1, a gene encoding calreticulin, partially suppresses necrotic cell death induced by mec-4 and deg-1 in C. elegans [10].…”

Section: Dear Editormentioning

confidence: 99%

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Dopamine neuron degeneration induced by MPP+ is independent of CED-4 pathway in Caenorhabditis elegans

2008

Cell Res

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Dear Editor,Parkinson's disease (PD) is a common neurodegenerative disease characterized by progressive loss of dopamine neurons in the substantia nigra, and manifests the cardinal clinical symptoms of resting tremors, rigidity, bradykinesia, hyperkinesias and abnormal posture. In the 1980s a synthetic heroin contaminant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was discovered as a cause of parkinsonism in a group of drug addicts. Since then, mechanisms involved in 1-methyl-4-phenylpyridinium (MPP + )-induced neurotoxicity have been extensively studied in various animal models and cell cultures. MPTP is highly lipophilic and can easily cross the blood-brain barrier and cell membrane. MPTP is metabolized in glial cells by monoamine oxidase type B to its active ionic metabolite MPP + , which is then selectively taken up by dopamine neurons via dopamine transporter (DAT). Hitherto, it has not been clearly defined whether the cell death induced by MPP + is apoptotic and/or necrotic. Contradictory results have been obtained from the treatment with different doses of MPP + in different culture systems [1][2][3][4]. This study, therefore, aims at determining the cell death mechanisms underlying MPP + -induced dopamine neuron degeneration in vivo in a living animal model of Caenorhabditis elegans.C. elegans hermaphrodite contains eight dopamine neurons: four symmetrically arranged cephalic cells (CEPs, two dorsal and two ventral), two bilateral anterior deirids (ADEs) in the head, and two bilateral posterior deirids (PDEs) near the vulva. The processes of dopamine neurons run through the body and tail. Since C. elegans is transparent, using the green fluorescent protein (GFP) attached to the DAT gene promoter (Pdat-1::GFP) we can visualize the bodies and processes of dopamine neurons to study dopamine neuron degeneration in vivo. A number of mutant alleles related to apoptotic cell death and necrotic cell death genes are available in C. elegans, which afford us an opportunity to investigate the relationship between MPP + -induced dopamine neuron degeneration and cell death pathways in vivo using the living animal model.In order to investigate MPP + -induced neurotoxicity in dopamine neurons of C. elegans in vivo, we synchronized Pdat-1::GFP reporter strain BZ555 at L1 stage and incubated the worms in various concentrations of MPP + (from 0.25 to 1.0 mM) and observed the GFP-labeled dopamine neurons 24, 48, and 72 h after MPP + treatment. Dramatic changes of GFP fluorescence in dopamine neurons were detected in MPP + -treated worms, but not in vehicle-treated worms. By 24 h after MPP + treatment, the GFP signal of CEP and ADE dendrites was significantly reduced or lost with retention of GFP in cell soma ( Figure 1A-i, ii, iii). In addition, blebbing along the CEP and ADE processes and swelling in the dopamine cell bodies were observed in some worms ( Figure 1A-ii). By 48 h, GFP was completely lost in a part of dopamine neurons. By 72 h after incubation with 0.5 mM MPP + , we found that a few of the worms surv...

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Section: Dear Editorsupporting

confidence: 91%

Section: Dear Editormentioning

confidence: 99%

Dopamine neuron degeneration induced by MPP+ is independent of CED-4 pathway in Caenorhabditis elegans

2008

Cell Res

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“…Aspartyl proteases (ASPs), lysosome-associated membrane protein-1 (LMP-1) and vacuolar H + -ATPases (VHAs) have been implicated in lysosomal-mediated neurodegeneration in C. elegans. [51][52][53] The C. elegans ASP-1, ASP-2, ASP-5 and ASP-6 proteins are homologous to the lysosomal protease …”

Section: Do Not Distributementioning

confidence: 99%

Decreased Insulin-Receptor Signaling Promotes the Autophagic Degradation of β-Amyloid Peptide inC. elegans

Florez-McClure¹,

Hohsfield²,

Fonte³

et al. 2007

Autophagy

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104

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Autophagy is a conserved membrane trafficking pathway that mediates the delivery of cytoplasmic substrates to the lysosome for degradation. Impaired autophagic function is implicated in the pathology of various neurodegenerative diseases. We have generated transgenic C. elegans that express human β-amyloid peptide (Aβ) in order to examine the mechanism(s) of Aβ-toxicity. In this model, Aβ expression causes autophagosome accumulation, thereby mimicking a pathology found in brains of Alzheimer's disease patients. Furthermore, we demonstrate that decreased insulin-receptor signaling [using the daf-2(e1370) mutation] suppresses Aβ-induced paralysis by a mechanism that requires autophagy. Surprisingly, the daf-2 mutation also decreases Aβ-induced autophagosome accumulation. These observations can be explained by a model in which decreased insulin-receptor signaling promotes the maturation of autophagosomes into degradative autolysosomes, whereas Aβ impairs this process. Consistent with this model, we find that RNAi-mediated knock-down of lysosomal components results in enhanced Aβ-toxicity and autophagosome accumulation. Also, Aβ; daf-2(e1370) nematodes contain more lysosomes than either Aβ or control strains. Finally, we demonstrate that decreased insulin-receptor signaling promotes the autophagic degradation of Aβ.

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“…For example, several genes encoding putative proteins involved in the production of known cellular damaging agents were identified. These included proteins that alter cellular redox potential and pH, as well as proteins involved in the production of reactive oxygen species (ROS) (Kültz, 2005;Syntichaki et al, 2005;Dröse and Brandt, 2008). This was also confirmed by the qRT-PCR results, where the A. areolatum homologue of the NADH-quinone oxidoreductase was up-regulated only during the incompatible interaction.…”

Section: Discussionmentioning

confidence: 54%

Gene expression associated with vegetative incompatibility in Amylostereum areolatum

Nest¹,

Steenkamp²,

Slippers³

et al. 2011

Fungal Genetics and Biology

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In filamentous fungi, vegetative compatibility among individuals of the same species is determined by the genes encoded at the heterokaryon incompatibility (het) loci. The hyphae of genetically similar individuals that share the same allelic specificities at their het loci are able to fuse and intermingle, while different allelic specificities at the het loci result in cell death of the interacting hyphae. In this study, suppression subtractive hybridization (SSH) followed by pyrosequencing and quantitative reverse transcription PCR were used to identify genes that are selectively expressed when vegetatively incompatible individuals of Amylostereum areolatum interact. The SSH library contained genes associated with various cellular processes, including cell-cell adhesion, stress and defence responses, as well as cell death. Some of the transcripts encoded proteins that were previously implicated in the stress and defence responses associated with vegetative incompatibility. Other transcripts encoded proteins known to be associated with programmed cell death, but have not previously been linked with vegetative incompatibility.Results of this study have considerably increased our knowledge of the processes underlying vegetative incompatibility in Basidiomycetes in general and A. areolatum in particular.

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The Vacuolar H+-ATPase Mediates Intracellular Acidification Required for Neurodegeneration in C. elegans

Cited by 99 publications

References 29 publications

Dopamine neuron degeneration induced by MPP+ is independent of CED-4 pathway in Caenorhabditis elegans

Dopamine neuron degeneration induced by MPP+ is independent of CED-4 pathway in Caenorhabditis elegans

Decreased Insulin-Receptor Signaling Promotes the Autophagic Degradation of β-Amyloid Peptide inC. elegans

Gene expression associated with vegetative incompatibility in Amylostereum areolatum

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