Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations or multiplications in alpha-synuclein gene cause familial forms of Parkinson disease or dementia with Lewy bodies (LB), and the deposition of wild-type alpha-synuclein as LB occurs as a hallmark lesion of these disorders, collectively referred to as synucleinopathies, implicating alpha-synuclein in the pathogenesis of synucleinopathy. To identify modifier genes of alpha-synuclein-induced neurotoxicity, we conducted an RNAi screen in transgenic C. elegans (Tg worms) that overexpress human alpha-synuclein in a pan-neuronal manner. To enhance the RNAi effect in neurons, we crossed alpha-synuclein Tg worms with an RNAi-enhanced mutant eri-1 strain. We tested RNAi of 1673 genes related to nervous system or synaptic functions, and identified 10 genes that, upon knockdown, caused severe growth/motor abnormalities selectively in alpha-synuclein Tg worms. Among these were four genes (i.e. apa-2, aps-2, eps-8 and rab-7) related to the endocytic pathway, including two subunits of AP-2 complex. Consistent with the results by RNAi, crossing alpha-synuclein Tg worms with an aps-2 mutant resulted in severe growth arrest and motor dysfunction. alpha-Synuclein Tg worms displayed a decreased touch sensitivity upon RNAi of genes involved in synaptic vesicle endocytosis, and they also showed impaired neuromuscular transmission, suggesting that overexpression of alpha-synuclein caused a failure in uptake or recycling of synaptic vesicles. Furthermore, knockdown of apa-2, an AP-2 subunit, caused an accumulation of phosphorylated alpha-synuclein in neuronal cell bodies, mimicking synucleinopathy. Collectively, these findings raise a novel pathogenic link between endocytic pathway and alpha-synuclein-induced neurotoxicity in synucleinopathy.
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PMID:A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in alpha-synuclein transgenic C. elegans. 1861 32

Improvements to the diagnosis and treatment of Parkinson's disease (PD) are dependent upon knowledge about susceptibility factors that render populations at risk. In the process of attempting to identify novel genetic factors associated with PD, scientists have generated many lists of candidate genes, polymorphisms, and proteins that represent important advances, but these leads remain mechanistically undefined. Our work is aimed toward significantly narrowing such lists by exploiting the advantages of a simple animal model system. While humans have billions of neurons, the microscopic roundworm Caenorhabditis elegans has precisely 302, of which only eight produce dopamine (DA) in hemaphrodites. Expression of a human gene encoding the PD-associated protein, alpha-synuclein, in C. elegans DA neurons results in dosage and age-dependent neurodegeneration. Worms expressing human alpha-synuclein in DA neurons are isogenic and express both GFP and human alpha-synuclein under the DA transporter promoter (Pdat-1). The presence of GFP serves as a readily visualized marker for following DA neurodegeneration in these animals. We initially demonstrated that alpha-synuclein-induced DA neurodegeneration could be rescued in these animals by torsinA, a protein with molecular chaperone activity. Further, candidate PD-related genes identified in our lab via large-scale RNAi screening efforts using an alpha-synuclein misfolding assay were then over-expressed in C. elegans DA neurons. We determined that five of seven genes tested represented significant candidate modulators of PD as they rescued alpha-synuclein-induced DA neurodegeneration. Additionally, the Lindquist Lab (this issue of JoVE) has performed yeast screens whereby alpha-synuclein-dependent toxicity is used as a readout for genes that can enhance or suppress cytotoxicity. We subsequently examined the yeast candidate genes in our C. elegans alpha-synuclein-induced neurodegeneration assay and successfully validated many of these targets. Our methodology involves generation of a C. elegans DA neuron-specific expression vector using recombinational cloning of candidate gene cDNAs under control of the Pdat-1 promoter. These plasmids are then microinjected in wild-type (N2) worms, along with a selectable marker for successful transformation. Multiple stable transgenic lines producing the candidate protein in DA neurons are obtained and then independently crossed into the alpha-synuclein degenerative strain and assessed for neurodegeneration, at both the animal and individual neuron level, over the course of aging.
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PMID:Application of a C. elegans dopamine neuron degeneration assay for the validation of potential Parkinson's disease genes. 1906 12

This annual review focuses on invertebrate model organisms, which shed light on new mechanisms in aging and provide excellent systems for both genome-wide and in-depth analysis. This year, protein interaction networks have been used in a new bioinformatic approach to identify novel genes that extend replicative lifespan in yeast. In an extended approach, using a new, human protein interaction network, information from the invertebrates was used to identify new, candidate genes for lifespan extension and their orthologues were validated in the nematode Caenorhabditis elegans. Chemosensation of diffusible substances from bacteria has been shown to limit lifespan in C. elegans, while a systematic study of the different methods used to implement dietary restriction in the worm has shown that they involve mechanisms that are partially distinct and partially overlapping, providing important clarification for addressing whether or not they are conserved in other organisms. A new theoretical model for the evolution of rejuvenating cell division has shown that asymmetrical division for either cell size or for damaged cell constituents results in increased fitness for most realistic levels of cellular protein damage. Work on aging-related disease has both refined our understanding of the mechanisms underlying one route to the development of Parkinson's disease and has revealed that in worms, as in mice, dietary restriction is protective against cellular proteotoxicity. Two systematic studies genetically manipulating the superoxide dismutases of C. elegans support the idea that damage from superoxide plays little or no role in aging in this organism, and have prompted discussion of other kinds of damage and other kinds of mechanisms for producing aging-related decline in function.
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PMID:Some highlights of research on aging with invertebrates, 2009. 1955 90

The recent discovery of the genetic causes for Parkinson's disease (PD) is fruitful; however, the continuing revelation of PD-related genes is rapidly outpacing the functional characterization of the gene products. Although the discovery of multiple PD-related genes places PD as one of the most complex multigenetic diseases of the brain, it will undoubtedly facilitate the unfolding of a central pathogenic pathway and an understanding of the etiology of PD. Recent findings of pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) (PARK8) that are linked to the most common familial forms and some sporadic forms of PD provide a unique opportunity to gain insight into the pathogenesis of PD. Despite rapid growth in biochemical, structural and in vitro cell culture studies of LRRK2, the in vivo characterizations of LRRK2 function generally fall short and are largely limited to invertebrates. The investigation of LRRK2 or homologs of LRRK2 in nonmammalian models provides important clues with respect to the cellular functions of LRRK2, but an elucidation of the physiology and pathophysiology of LRRK2 relevant to PD would still depend on mammalian models established by multiple genetic approaches, followed by rigorous examination of the models for pathological process. This minireview summarizes previous studies of genes for ROCO and LRRK2 homologs in slime mold, nematode worms and fruit flies. It also discusses the results obtained from available mouse models of LRRK2 that begin to provide information for understanding LRRK2-mediated pathogenesis in PD.
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PMID:LRRK2 in Parkinson's disease: in vivo models and approaches for understanding pathogenic roles. 1980 14

DJ-1 is a neuroprotective gene mutated in recessive Parkinson's disease (PD). In addition to direct protective functions in neurons, DJ-1 regulates neuroinflammatory signaling in primary mouse brain astrocytes. To assess the influence of DJ-1 on innate immunity signaling in vivo, we have generated djr-1 knockout Caenorhabditis elegans. When grown on pathogenic gram-negative bacteria, djr-1 (-/-) worms showed stronger phosphorylation of p38 mitogen-activated protein kinase (PMK-1) and hyper-induction of PMK-1 target genes. Thus, PD-associated DJ-1 contributes to regulation of innate immunity.
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PMID:Parkinson's disease-associated DJ-1 modulates innate immunity signaling in Caenorhabditis elegans. 2037 9

Aging has been a subject of interest since primordial times. More recently, it became clear that aging is the major known risk factor for several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease. A major focus in the field of aging is to examine whether the genetic regulators of lifespan also regulate the trigger and/or progression of age-related disorders. Sirtuins, which belong to the Sir2 family of NAD(+)-dependent deacetylases, are known to regulate longevity in yeast, worms, and flies. In mammals, there are seven homologs of the yeast Sir2, Sirt1-7. Therefore, the challenge now is to unravel howthe seven mammalian Sir2 proteins communicate to regulate the cross talk between aging and the onset and progression of age-related disorders. Here, we review how sirtuins contribute for aging and, in particular, for neurodegeneration and how they are becoming attractive targets for therapeutic intervention.
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PMID:Sirtuins: common targets in aging and in neurodegeneration. 2084 69

Significant limitations in vertebrate animal model systems include the time involved, the expense, the fact that in vitro results may not reflect live animal pathology, difficulties in transporting the toxin past the blood brain barrier, and the inability to identify the mechanism of action without some a priori knowledge of the toxin's target. The availability of the complete genome sequence of the nematode C. elegans, coupled with the worm's size, growth rate, ease of culturing, and the realization that basic biological mechanisms and disease processes between worms and humans are highly conserved, makes this genetically tractable model a remarkable opportunity to dissect and identify in vivo the cellular processes involved in toxin-induced cell dysregulation and death. This unit includes protocols for culturing worms on solid and axenic media and acute and chronic exposure parameters for Parkinson's disease-associated toxins and hemin chloride. These methods provide the groundwork for using this powerful model system to further elucidate and understand the molecular mechanisms involved in nutrition as well as toxicological responses relevant to human diseases.
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PMID:The nematode C. elegans as an animal model to explore toxicology in vivo: solid and axenic growth culture conditions and compound exposure parameters. 2092 56

The vascular network is closely linked to the neural system, and an interdependence is displayed in healthy and in pathophysiological responses. How has close apposition of two such functionally different systems occurred? Here, we present a hypothesis for the evolution of the vascular network from an ancestral neural guidance system. Biological cornerstones of this hypothesis are the vascular endothelial growth factor (VEGF) protein family and cognate receptors. The primary sequences of such proteins are conserved from invertebrates, such as worms and flies that lack discernible vascular systems compared to mammals, but all these systems have sophisticated neuronal wiring involving such molecules. Ancestral VEGFs and receptors (VEGFRs) could have been used to develop and maintain the nervous system in primitive eukaryotes. During evolution, the demands of increased morphological complexity required systems for transporting molecules and cells, i.e., biological conductive tubes. We propose that the VEGF-VEGFR axis was subverted by evolution to mediate the formation of biological tubes necessary for transport of fluids, e.g., blood. Increasingly, there is evidence that aberrant VEGF-mediated responses are also linked to neuronal dysfunctions ranging from motor neuron disease, stroke, Parkinson's disease, Alzheimer's disease, ischemic brain disease, epilepsy, multiple sclerosis, and neuronal repair after injury, as well as common vascular diseases (e.g., retinal disease). Manipulation and correction of the VEGF response in different neural tissues could be an effective strategy to treat different neurological diseases.
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PMID:Evolution of the VEGF-regulated vascular network from a neural guidance system. 2127 3

Epidemiological evidence suggests positive correlations between pesticide usage and the incidence of Parkinson's disease (PD). To further explore this relationship, we used wild type (N2) Caenorhabditis elegans (C. elegans) to test the following hypothesis: Exposure to a glyphosate-containing herbicide (TD) and/or a manganese/zinc ethylene-bis-dithiocarbamate-containing fungicide (MZ) may lead to neurotoxicity. We exposed N2 worms to varying concentrations of TD or MZ for 30 min (acute) or 24h (chronic). To replicate agricultural usage, a third population was exposed to TD (acute) followed by MZ (acute). For acute TD exposure, the LC(50)=8.0% (r(2)=0.6890), while the chronic LC(50)=5.7% (r(2)=0.9433). Acute MZ exposure led to an LC(50)=0.22% (r(2)=0.5093), and chronic LC(50)=0.50% (r(2)=0.9733). The combined treatment for TD+MZ yielded an LC(50)=12.5% (r(2)=0.6367). Further studies in NW1229 worms, a pan-neuronally green fluorescent protein (GFP) tagged strain, indicated a statistically significant (p<0.05) and dose-dependent reduction in green pixel number in neurons of treated worms following each paradigm. This reduction of pixel number was accompanied by visual neurodegeneration in photomicrographs. For the dual treatment, Bliss analysis suggested synergistic interactions. Taken together, these data suggest neuronal degeneration occurs in C. elegans following treatment with environmentally relevant concentrations of TD or MZ.
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PMID:Exposure to Mn/Zn ethylene-bis-dithiocarbamate and glyphosate pesticides leads to neurodegeneration in Caenorhabditis elegans. 2137 51

Parkinson's disease (PD) is the second most common neurodegenerative disorder and is mainly characterized by the selective and progressive loss of dopaminergic neurons, accompanied by locomotor defects. Although most PD cases are sporadic, several genes are associated with rare familial forms of the disease. Analyses of their function have provided important insights into the disease process, demonstrating that three types of cellular defects are mainly involved in the formation and/or progression of PD: abnormal protein aggregation, oxidative damage, and mitochondrial dysfunction. These studies have been mainly performed in PD models created in mice, fruit flies, and worms. Among them, Drosophila has emerged as a very valuable model organism in the study of either toxin-induced or genetically linked PD. Indeed, many of the existing fly PD models exhibit key features of the disease and have been instrumental to discover pathways relevant for PD pathogenesis, which could facilitate the development of therapeutic strategies.
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PMID:Drosophila models of Parkinson's disease: discovering relevant pathways and novel therapeutic strategies. 2151 85


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