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Prion protein in Caenorhabditis elegans: Distinct models of anti-BAX and neuropathology.

ABSTRACT: The infectious agent of prion diseases is believed to be nucleic acid-free particles composed of misfolded conformational isomers of a host protein known as prion protein (PrP). Although this "protein-only" concept is generally accepted, decades of extensive research have not been able to elucidate the mechanisms by which PrP misfolding leads to neurodegeneration and infectivity. The challenges in studying prion diseases relate in part to the limitations of mammalian prion models, which include the long incubation period post-infection until symptoms develop, the high expense of maintaining mammals for extended periods, as well as safety issues. In order to develop prion models incorporating a genetically tractable simple system with a well-defined neuronal system, we generated transgenic C. elegans expressing the mouse PrP behind the pan-neuronal ric-19 promoter (Pric-19). We show here that high expression of Pric-19::PrP in C. elegans can result in altered morphology, defective mobility, and shortened lifespan. Low expression of Pric-19::PrP, however, does not cause any detectable harm. Using the dopamine neuron specific promoter Pdat-1, we also show that expression of the murine BAX, a pro-apoptotic member of the Bcl-2 family, causes dopamine neuron destruction in the nematode. However, co-expression of PrP inhibits BAX-mediated dopamine neuron degeneration, demonstrating for the first time that PrP has anti-BAX activity in living animals. Thus, these distinct PrP-transgenic C. elegans lines recapitulate a number of functional and neuropathological features of mammalian prion models, and provide an opportunity for facile identification of genetic and environmental contributors to prion-associated pathology.

SUBMITTER: Park KW

PROVIDER: S-EPMC3038003 | biostudies-literature | 2011 Jan-Mar

REPOSITORIES: biostudies-literature

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Prion protein in Caenorhabditis elegans: Distinct models of anti-BAX and neuropathology.

Park Kyung-Won KW Li Liming L

Prion 20110101 1

The infectious agent of prion diseases is believed to be nucleic acid-free particles composed of misfolded conformational isomers of a host protein known as prion protein (PrP). Although this "protein-only" concept is generally accepted, decades of extensive research have not been able to elucidate the mechanisms by which PrP misfolding leads to neurodegeneration and infectivity. The challenges in studying prion diseases relate in part to the limitations of mammalian prion models, which include ...[more]

PMID: 21084837

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Project description:Perfluorooctane sulfonate (PFOS) has been widely utilized in numerous industries. Due to long environmental and biological half-lives, PFOS is a major public health concern. Although the literature suggests that PFOS may induce neurotoxicity, neurotoxic mechanisms, and neuropathology are poorly understood. Thus, the primary goal of this study was to determine if PFOS is selectively neurotoxic and potentially relevant to specific neurological diseases. Nematodes (Caenorhabditis elegans) were exposed to PFOS or related per- and polyfluoroalkyl substances (PFAS) for 72 h and tested for evidence of neuropathology through examination of cholinergic, dopaminergic, gamma-amino butyric acid (GABA)ergic, and serotoninergic neuronal morphologies. Dopaminergic and cholinergic functional analyses were assessed through 1-nonanol and Aldicarb assay. Mechanistic studies assessed total reactive oxygen species, superoxide ions, and mitochondrial content. Finally, therapeutic approaches were utilized to further examine pathogenic mechanisms. Dopaminergic neuropathology occurred at lower exposure levels (25 ppm, approximately 50 µM) than required to produce neuropathology in GABAergic, serotonergic, and cholinergic neurons (100 ppm, approximately 200 µM). Further, PFOS exposure led to dopamine-dependent functional deficits, without altering acetylcholine-dependent paralysis. Mitochondrial content was affected by PFOS at far lower exposure level than required to induce pathology (≥1 ppm, approximately 2 µM). Perfluorooctane sulfonate exposure also enhanced oxidative stress. Further, mutation in mitochondrial superoxide dismutase rendered animals more vulnerable. Neuroprotective approaches such as antioxidants, PFAS-protein dissociation, and targeted (mitochondrial) radical and electron scavenging were neuroprotective, suggesting specific mechanisms of action. In general, other tested PFAS were less neurotoxic. The primary impact is to prompt research into potential adverse outcomes related to PFAS-induced dopaminergic neurotoxicity in humans.

Project description:BackgroundThe wide use of organophosphorus (OP) pesticides makes them an important public health concern. Persistent effects of exposure and the mechanism of neuronal degeneration are continuing issues in OP toxicology. To elucidate early steps in the mechanisms of OP toxicity, we studied alterations in global gene and protein expression in Caenorhabditis elegans exposed to OPs using microarrays and mass spectrometry. We tested two structurally distinct OPs (dichlorvos and fenamiphos) and employed a mechanistically different third neurotoxicant, mefloquine, as an out-group for analysis. Treatment levels used concentrations of chemical sufficient to prevent the development of 10%, 50% or 90% of mid-vulval L4 larvae into early gravid adults (EGA) at 24 h after exposure in a defined, bacteria-free medium.ResultsAfter 8 h of exposure, the expression of 87 genes responded specifically to OP treatment. The abundance of 34 proteins also changed in OP-exposed worms. Many of the genes and proteins affected by the OPs are expressed in neuronal and muscle tissues and are involved in lipid metabolism, cell adhesion, apoptosis/cell death, and detoxification. Twenty-two genes were differentially affected by the two OPs; a large proportion of these genes encode cytochrome P450s, UDP-glucuronosyl/UDP-glucosyltransferases, or P-glycoproteins. The abundance of transcripts and the proteins they encode were well correlated.ConclusionExposure to OPs elicits a pattern of changes in gene expression in exposed worms distinct from that of the unrelated neurotoxicant, mefloquine. The functional roles and the tissue location of the genes and proteins whose expression is modulated in response to exposure is consistent with the known effects of OPs, including damage to muscle due to persistent hypercontraction, neuronal cell death, and phase I and phase II detoxification. Further, the two different OPs evoked distinguishable changes in gene expression; about half the differences are in genes involved in detoxification, likely reflecting differences in the chemical structure of the two OPs. Changes in the expression of a number of sequences of unknown function were also discovered, and these molecules could provide insight into novel mechanisms of OP toxicity or adaptation in future studies.

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Prion protein in Caenorhabditis elegans: Distinct models of anti-BAX and neuropathology.

Publications

Prion protein in Caenorhabditis elegans: Distinct models of anti-BAX and neuropathology.

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