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Mov Disord,
2011]
Background: Parkinson's disease is a progressive neurodegenerative disorder mainly characterized by the loss of dopaminergic neurons from the substantia nigra pars compacta and the presence, in the affected brain regions, of protein inclusions named Lewy Bodies. Despite the fact that numerous mutations causing hereditary forms of Parkinson's disease have been identified in the last decade, current transgenic animal models do not adequately reproduce cardinal features of the human disease. Altogether, the animal models derived of human mutations indicate that the nigrostriatal degenerative process results from the combination of several mechanisms that implicate mitochondrial dysfunction, oxidative damage, and protein degradation impairment.Methods and Results: We performed a literature search between 2008 and 2010.Discussion: The absence of adequate in vivo experimental models of Parkinson's disease has severe repercussions for therapeutic intervention success for this incurable neurodegenerative disorder. The present nonexhaustive review looks at invertebrate and mammalian models of Parkinson's disease generated in the last three years.
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Exp Neurol,
2013]
Neurodegenerative diseases which include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and others are becoming an increasing threat to human health worldwide. The degeneration and death of certain specific groups of neurons are the hallmarks of these diseases. Despite the research progress in identification of several disease-related genes, the mechanisms underlying the neurodegeneration in these diseases remain unclear. Given the molecular conservation in neuronal signaling between Caenorhabditis elegans and vertebrates, an increasing number of research scientists have used the nematode to study this group of diseases. This review paper will focus on the model system that has been established in C. elegans to investigate the pathogenetic roles of those reported disease-related genes in AD, PD, ALS, HD and others. The progress in C. elegans provides useful information of the genetic interactions and molecular pathways that are critical in the disease process, and may help better our understanding of the disease mechanisms and search for new therapeutics for these devastating diseases.
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EMBO Mol Med,
2009]
Various age-related neurodegenerative diseases, including Parkinson's disease, polyglutamine expansion diseases and Alzheimer's disease, are associated with the accumulation of misfolded proteins in aggregates in the brain. How and why these proteins form aggregates and cause disease is still poorly understood. Small model organisms--the baker's yeast Saccharomyces cerevisiae, the nematode worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster--have been used to model these diseases and high-throughput genetic screens using these models have led to the identification of a large number of genes that modify aggregation and toxicity of the disease proteins. In this review, we revisit these models and provide a comprehensive comparison of the genetic screens performed so far. Our integrative analysis highlights alterations of a wide variety of basic cellular processes. Not all disease proteins are influenced by alterations in the same cellular processes and despite the unifying theme of protein misfolding and aggregation, the pathology of each of the age-related misfolding disorders can be induced or influenced by a disease-protein-specific subset of molecular processes.
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Ageing Res Rev,
2023]
Neurodegenerative diseases (NDs) are a heterogeneous group of aging-associated ailments characterized by interrupting cellular proteostasic machinery and the misfolding of distinct proteins to form toxic aggregates in neurons. Neurodegenerative diseases, which include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and others, are becoming an increasing threat to human health worldwide. The degeneration and death of certain specific groups of neurons are the hallmarks of these diseases. Over the past decades, Caenorhabditis eleganshas beenwidely used as a transgenic model to investigate biological processes related to health and disease. The nematode Caenorhabditis elegans (C. elegans) has developed as a powerful tool for studying disease mechanisms due to its ease of genetic handling and instant cultivation while providing a whole-animal system amendable to several molecular and biochemical techniques. In this review, we elucidate the potential of C. elegans as a versatile platform for systematic dissection of the molecular basis of human disease, focusing on neurodegenerative disorders, and may help better our understanding of the disease mechanisms and search for new therapeutics for these devastating diseases.
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Philos Trans R Soc Lond B Biol Sci,
2011]
Inhibiting insulin/IGF-1 signalling extends lifespan and delays age-related disease in species throughout the animal kingdom. This life-extension pathway, the first to be defined, was discovered through genetic studies in the small roundworm Caenorhabditis elegans. This discovery is described here.
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Future Sci OA,
2015]
Experimental model systems have long been used to probe the causes, consequences and mechanisms of pathology leading to human disease. Ideally, such information can be exploited to inform the development of therapeutic strategies or treatments to combat disease progression. In the case of protein misfolding diseases, a wide range of model systems have been developed to investigate different aspects of disorders including Huntington's disease, Parkinson's disease, Alzheimer's disease as well as amyotrophic lateral sclerosis. Utility of these systems broadly correlates with evolutionary complexity: small animal models such as rodents and the fruit fly are appropriate for pharmacological modeling and cognitive/behavioral assessment, the roundworm Caenorhabditis elegans allows analysis of tissue-specific disease features, and unicellular organisms such as the yeast Saccharomyces cerevisiae and the bacterium Escherichia coli are ideal for molecular studies. In this chapter, we highlight key advances in our understanding of protein misfolding/unfolding disease provided by model systems.
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Prog Mol Biol Transl Sci,
2011]
Caenorhabditis elegans is increasingly being used to study neurodegenerative diseases. Nematodes are translucent, which facilitates study of particular neurons in the living animal, and easy to manipulate genetically. Despite vast evolutionary divergence, human proteins are functionally active when expressed in C. elegans, and disease-linked mutations in these proteins also cause phenotypic changes in the nematode. In this chapter, we review use of C. elegans to investigate the pathophysiology of Alzheimer's disease, Parkinson's disease, and axonal degeneration. Studies of presenilin, -amyloid, tau, -synuclein, and LRRK2 all produce strong phenotypic effects in C. elegans, and in many cases reproduce selective neuronal vulnerability observed in humans. Disease-linked mutations enhance degeneration in the C. elegans models. These studies are increasingly leading to high-throughput screens that identify novel genes and novel pharmaceuticals that modify the disease course.
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Int J Mol Sci,
2020]
Parkinson's disease (PD) is the most common movement disorder with motor and nonmotor signs. The current therapeutic regimen for PD is mainly symptomatic as the etio-pathophysiology has not been fully elucidated. A variety of animal models has been generated to study different aspects of the disease for understanding the pathogenesis and therapeutic development. The disease model can be generated through neurotoxin-based or genetic-based approaches in a wide range of animals such as non-human primates (NHP), rodents, zebrafish, <i>Caenorhabditis</i> (<i>C.</i>) <i>elegans</i>, and drosophila. Cellular-based disease model is frequently used because of the ease of manipulation and suitability for large-screen assays. In neurotoxin-induced models, chemicals such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and paraquat are used to recapitulate the disease. Genetic manipulation of PD-related genes, such as -Synuclein(SNCA), Leucine-rich repeat kinase 2 (LRRK2), Pten-Induced Kinase 1 (PINK1), Parkin(PRKN), and Protein deglycase (DJ-1) Are used in the transgenic models. An emerging model that combines both genetic- and neurotoxin-based methods has been generated to study the role of the immune system in the pathogenesis of PD. Here, we discuss the advantages and limitations of the different PD models and their utility for different research purposes.
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Dev Dyn,
2010]
Parkinson's disease (PD) is an age-related movement disorder resulting, in part, from selective loss of dopaminergic neurons. Both invertebrate and mammalian models have been developed to study the cellular mechanisms altered during disease progression; nevertheless there are limitations within each model. Mammalian models remain invaluable in studying PD, but are expensive and time consuming. Here, we review genetic and environmental factors associated with PD, and describe how the nematode roundworm, Caenorhabditis elegans, has been used as a model organism for studying various aspects of this neurodegenerative disease. Both genetic and chemical screens have been conducted in C. elegans to identify molecular pathways, proteins, and small molecules that can impact PD pathology. Lastly, we highlight future areas of investigation, in the context of emerging fields in biology, where the nematode can be exploited to provide mechanistic insights and potential strategies to accelerate the path toward possible therapeutic intervention for PD.
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Metallomics,
2011]
Neurodegeneration is characterized by the cell death or loss of structure and/or function of neurons. Many neurodegenerative diseases including Parkinson's disease (PD) and Alzheimer's disease (AD) are the result of neurodegenerative processes. Metals are essential for many life processes, but they are also culpable for several neurodegenerative mechanisms. In this review, we discuss the role of metals in neurodegenerative diseases with emphasis on the utility of Caenorhabditis elegans (C. elegans) genetic models in deciphering mechanisms associated with the etiology of PD and AD.