The<i>Caenorhabditis elegans</i>Dopaminergic System: Opportunities for Insights into Dopamine Transport and Neurodegeneration

Nass, Richard; Blakely, Randy D.

doi:10.1146/annurev.pharmtox.43.100901.135934

Cited by 99 publications

(73 citation statements)

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“…All of the genes responsible for DA biosynthesis, packaging, and reuptake have recognizable homologs in the worm genome, and genetic, cellular, and functional studies confirm their participation in dopaminergic function (47). Transcriptional green fluorescent protein (GFP) fusions allow the eight DA neurons to be clearly visible in vivo under a fluorescent dissecting scope, and, as in vertebrates, the neurotoxicants 6-hydroxy dopamine (6-OHDA), 1-methyl-4-phenylpyridinium, and rotenone can confer DA neurodegeneration (48,49).…”

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confidence: 91%

The Divalent Metal Transporter Homologues SMF-1/2 Mediate Dopamine Neuron Sensitivity in Caenorhabditis elegans Models of Manganism and Parkinson Disease

Settivari

LeVora

Nass

2009

Journal of Biological Chemistry

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119

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Parkinson disease (PD) and manganism are characterized by motor deficits and a loss of dopamine (DA) neurons in the substantia nigra pars compacta. Epidemiological studies indicate significant correlations between manganese exposure and the propensity to develop PD. The vertebrate divalent metal transporter-1 (DMT-1) contributes to maintaining cellular Mn 2؉ homeostasis and has recently been implicated in Fe 2؉ -mediated neurodegeneration in PD. In this study we describe a novel model for manganism that incorporates the genetically tractable nematode Caenorhabditis elegans. We show that a brief exposure to Mn 2؉ increases reactive oxygen species and glutathione production, decreases oxygen consumption and head mitochondria membrane potential, and confers DA neuronal death. DA neurodegeneration is partially dependent on a putative homologue to DMT-1, SMF-1, as genetic knockdown or deletion partially inhibits the neuronal death. Mn 2؉ also amplifies the DA neurotoxicity of the PD-associated protein ␣-synuclein. Furthermore, both SMF-1 and SMF-2 are expressed in DA neurons and contribute to PD-associated neurotoxicant-induced DA neuron death. These studies describe a C. elegans model for manganism and show that DMT-1 homologues contribute to Mn 2؉ -and PD-associated DA neuron vulnerability.Manganese is the second most prevalent transition metal and is an essential trace element that is necessary for normal growth and development. The heavy metal is required for a number of biological processes, including amino acid, lipid, and carbohydrate production, and metabolism, and is a cofactor for a diverse set of proteins, including arginases, transferases, hydrolases, ligases, and oxidoreductases (1, 2). Deficiencies in Mn 2ϩ , although rare, have been linked with bone malformation, hypertension, osteoporosis, and epilepsy (3, 4). Mn 2ϩ is also a potent neurotoxicant, and occupational exposure to high concentrations of the metal can result in a neurological condition called manganism (1, 5). Symptoms of manganism include tremors, bradykinesia, rigidity, and facial muscle spasms (1, 6, 7). Mn 2ϩ neurotoxicity has been associated with a number of occupational and environmental exposures. High incidence of manganism has been found in manganese miners and smelters (7-10). Welders appear to be particularly vulnerable to the disorder as manganese alloys used in the heating and joining of metals may result in the production and inhalation of manganese particles (11). Exposure to Mn 2ϩ -based pesticides, including maneb and mancozeb, has also been associated with the development of manganism (12)(13)(14). Furthermore, significant environmental exposures have been reported with water contamination and possibly with the manganese-containing anti-knock fuel additive methylcyclopentadienyl manganese tricarbonyl (12). Recently, high exposures to Mn 2ϩ have also been associated with psychoactive stimulant preparations for recreational drug use (15,16).Epidemiological studies suggest a significant correlation of exposure to high concent...

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confidence: 91%

The Divalent Metal Transporter Homologues SMF-1/2 Mediate Dopamine Neuron Sensitivity in Caenorhabditis elegans Models of Manganism and Parkinson Disease

Settivari

LeVora

Nass

2009

Journal of Biological Chemistry

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119

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“…In addition, three pairs of gender-specific dopaminergic neurons are present in the male tail (Sulston et al, 1975). The mammalian neuronal proteins involved in DA synthesis, vesicle loading, and reuptake all have C. elegans homologs, and mutants for each of these homologs have been described previously (Wintle and Van Tol, 2001;Nass and Blakely, 2003). Sawin et al (2000) showed that exogenous DA has inhibitory effects on C. elegans motor behavior.…”

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confidence: 99%

Molecular Mechanisms of Amphetamine Actions in Caenorhabditis elegans

Carvelli

Matthies²,

Galli³

2010

Mol Pharmacol

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Amphetamine (AMPH) poses a serious hazard to public health. Defining the molecular targets of AMPH is essential to developing treatments for psychostimulant abuse. AMPH elicits its behavioral effects primarily by increasing extracellular dopamine (DA) levels through the reversal of the DA transporter (DAT) cycle and, as a consequence, altering DA signaling. In Caenorhabditis elegans, an excess of synaptic DA results in a loss of motility in water, termed swimming-induced paralysis (SWIP). Here we demonstrate that AMPH produces SWIP in a time-and dose-dependent manner in wild-type (wt) animals but has a reduced ability to generate SWIP in DAT knock out worms (dat-1). To determine whether D1-like and/or D2-like receptors are involved in AMPH-induced SWIP, we performed experiments in DOP-1 and DOP-4, and DOP-2, and DOP-3 receptor knockout animals, respectively. AMPH administration resulted in a reduced ability to induce SWIP in animals lacking DOP-3, DOP-4, and DOP-2 receptors. In contrast, in worms lacking DOP-1 receptors, AMPH-induced SWIP occurred at wt levels. Using microamperometry on C. elegans DA neurons, we determined that in contrast to wt cells, AMPH failed to promote DA efflux in dat-1 DA neurons. These data suggest that DA efflux is critical to sustaining SWIP behavior by signaling through DOP-3, DOP-4, and DOP-2. In a double mutant lacking both DAT-1 and DOP-1 expression, we found no ability of AMPH to induce SWIP or DA efflux. This result supports the paradigm that DA efflux through C. elegans DAT is required for AMPH-induced behaviors and does not require DOP-1 signaling.Dysfunction in DA signaling has been implicated in multiple pathologies, including schizophrenia, attention-deficit/ hyperactivity disorder, Parkinson's disease, and AMPH abuse. Although it is well known that dopaminergic pathways are involved in cocaine and AMPH abuse, a comprehensive understanding of the key players coordinating AMPH behaviors is still missing. Upon exocytotic release of DA into the synapse, DATs coordinate the spatial and temporal action of DA by actively clearing the amine from the extracellular space. Although diffusion and enzymatic degradation may partially govern the synaptic concentration of DA, knockout studies have established DAT function as the primary mechanism controlling extracellular DA levels. DAT is the major molecular target responsible for the reward properties and abuse potential of several psychostimulants, including cocaine, methamphetamine, and AMPH. As a substrate of DAT, AMPH elevates extracellular DA levels by antagonizing DA clearance and stimulating DAT-mediated DA efflux. The subsequent increase in dopaminergic signaling mediated by DA receptors leads to secondary plasticity that mediates addiction. Whereas multiple lines of evidence implicate DA receptors in the mechanism of action of abused psychostimulants such as AMPH (Hiroi and White, 1991;Vallone et al., 2000;Ball et al., 2003), the degree to which different receptors support AMPH-induced behaviors has not yet been complet...

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“…elegans is a powerful genetic model for exploring the molecular mechanisms of neuron function and human disease (Riddle et al, 1997;Nass et al, 2001). The worm's nervous system contains almost all of the known signaling and neurotransmitter systems found in the vertebrates (Bargmann, 1998;Nass and Blakely, 2003). Its genome has been sequenced and contains approximately 20,000 genes, over 90% of the human genome.…”

Section: Discussionmentioning

confidence: 99%

“…For example, in one forward genetic screen we could utilize our DAT-1::GFP reporter line to identify molecules involved in Mn 2+ -induced neuronal death. We would first mutagenize the genome of the parental animals and then isolate the second generation hermaphrodites (to homozygose the mutation; Nass et al, 2003) in which GFP is still retained in the DA neurons following exposure to Mn 2+ . Animals that have DA neurons that are insensitive to Mn 2+ could have mutations within Mn 2+ transport proteins or proteins involved in DA neuron viability or cell death.…”

Section: Discussionmentioning

confidence: 99%

Use of non-mammalian alternative models for neurotoxicological study

et al. 2008

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The field of neurotoxicology needs to satisfy two opposing demands: the testing of a growing list of chemicals, and resource limitations and ethical concerns associated with testing using traditional mammalian species. National and international government agencies have defined a need to reduce, refine or replace mammalian species in toxicological testing with alternative testing methods and non-mammalian models. Toxicological assays using alternative animal models may relieve some of this pressure by allowing testing of more compounds while reducing expense and using fewer mammals. Recent advances in genetic technologies and the strong conservation between human and non-mammalian genomes allows for the dissection of the molecular pathways involved in neurotoxicological responses and neurological diseases using genetically tractable organisms. In this review, applications of four non-mammalian species, Zebrafish, cockroach, Drosophila, and Caenorhabditis elegans, in the investigation of neurotoxicology and neurological diseases are presented.

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TheCaenorhabditis elegansDopaminergic System: Opportunities for Insights into Dopamine Transport and Neurodegeneration

Cited by 99 publications

References 146 publications

The Divalent Metal Transporter Homologues SMF-1/2 Mediate Dopamine Neuron Sensitivity in Caenorhabditis elegans Models of Manganism and Parkinson Disease

The Divalent Metal Transporter Homologues SMF-1/2 Mediate Dopamine Neuron Sensitivity in Caenorhabditis elegans Models of Manganism and Parkinson Disease

Molecular Mechanisms of Amphetamine Actions in Caenorhabditis elegans

Use of non-mammalian alternative models for neurotoxicological study

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