Conn Progress in Nucleic Acid Research and Molecular Biology

1. Auflage 2011
ISBN: 978-0-08-092327-7
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, Band Volume 82, 272 Seiten

Reihe: Progress in Nucleic Acid Research and Molecular Biology

Nucleic acids are the fundamental building blocks of DNA and RNA and are found in virtually every living cell. Molecular biology is a branch of science that studies the physicochemical properties of molecules in a cell, including nucleic acids, proteins, and enzymes. Increased understanding of nucleic acids and their role in molecular biology will further many of the biological sciences, including genetics, biochemistry, and cell biology. Progress in Nucleic Acid Research and Molecular Biology is intended to bring to light the most recent advances in these overlapping disciplines with a timely compilation of reviews comprising each volume. - This series provides a forum for discussion of new discoveries, approaches, and ideas - Contributions from leading scholars and industry experts - Reference guide for researchers involved in molecular biology and related fields

Autoren/Hrsg.

Conn, P. Michael

Leseproben

Drosophila Orthologues to Human Disease Genes: An Update on Progress

Sergey Doronkin; Lawrence T. Reiter    Department of Neurology, Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163

Publisher Summary

This chapter presents a broader view of the state of human disease modeling in Drosophila melanogaster and discusses new directions in the study of the genetic basis of human disorders in flies. The Drosophila classical genetics powerhouse, in combination with rapidly developing genomic and postgenomic tools, accelerates the identification and characterization of gene networks. Because the molecular mechanisms controlling a variety of physiological pathways are largely conserved between flies and humans, flies are quite useful in modeling a variety of human diseases. These include nervous system disorders, cancer, immune responses, elements of the cardiovascular system, and many more. Possibly the most successful area of human neurological disease modeling in Drosophila is the models of polyglutamine tract repeat disorders. The fly eye is an excellent readout for polyglutamine tract repeat disorders, like such as Huntington’s disease and the spinocerebellar ataxias. In both conditions, there is a critical threshold of polyglutamine repeats that must be reached before a clinical presentation is observed. In flies, the expression of the human Huntingtin protein or the SCA3/MJD protein, containing the clinically relevant number of repeats, leads to the degeneration of photoreceptor neurons.

Modeling human disease in flies is possible because many basic processes of cellular proliferation, motility, regulation and interaction are highly conserved among multicellular organisms. Despite years of extensive study, a clear understanding of the basic biology of many human illnesses still remains elusive. In part, this is due to a deficit in adequate genetic model systems to study pathogenesis of disease dynamics in a developing organism. Drosophila melanogaster is emerging as a model of choice to study the molecular genetic underpinnings of human disease. It should be noted as well that the selection of Drosophila to model human genetic disease is not only based on homology, but also on the wide variety of tools and a century of classic genetics that provide outstanding experimental capabilities. Recent advances in methodology have increased the value of this model system to study the basic science of human disease and opened up new opportunities. The elucidation in flies of the underlying regulated mechanisms of human disorders may eventually reveal new therapeutic targets for the treatment of diseases. Here we describe recent advances in the study of neurological disorders, blood diseases and even cancer. We also outline future directions in research on modeling many devastating diseases in the fruit fly Drosophila melanogaster.

I Introduction

The goal of this chapter is to present to a broader view of the state of human disease modeling in Drosophila melanogaster and to outline new directions in the study of the genetic basis of human disorders in flies. The Drosophila classical genetics powerhouse in combination with rapidly developing genomic and postgenomic tools accelerates the identification and characterization of gene networks. Because the molecular mechanisms controlling a variety of physiological pathways are largely conserved between flies and humans, flies are quite useful in modeling a variety of human diseases. These include nervous system disorders, cancer, immune responses, elements of the cardiovascular system, and many more (1). In addition, Drosophila genetic tools can also be used to study systems that are not evolutionally conserved or common between flies and humans. In fact, fly genetics has been applied to the dissection of certain basic metabolic pathways in human organs that are not even present or undeveloped in flies. Due to obvious anatomical differences, the humble fruit fly certainly will never compete with mammalian models in every aspect of human diseases research, but a century of fly genetics should not be underestimated. As a genetic model organism, Drosophila has much to offer human disease researchers in terms of genetic screening power, a wide variety of molecular tools, multiple stock centers packed with a variety of allele, transgene, and deficiency collections and at the same time, any fly geneticist will tell you that they offer an elegant simplicity that drives basic research discoveries even in inexperienced student investigators.

II Neurological Disease

In terms of modeling human genetic disease in Drosophila, neurological diseases have been the most lucrative [reviewed in (2, 3)]. This is not surprising considering a significant level of sequence and function conservation of nervous system genes and pathways that are directly relevant to human neurological disease [links between human disease and fly genes can be found using the Homophila database at http://homophila.sdsc.edu; (1, 4)]. Although the basic processes of neurogenesis, neuronal pathfinding, and synaptogenesis have been studied in Drosophila for some time, recently, there has been a boost in Drosophila research focusing directly on models for neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, spinocerebellar ataxias, and Huntington’s disease. These efforts have not only contributed to a better understanding of the underlying basic genetic and molecular mechanisms of these disorders but also opened new avenues for practical pharmacotherapy and potential drug screening.

Contemporary genetic studies imply misexpression of the gene for a-synuclein in familial forms of Parkinson’s disease. The common symptoms of this locomotion disorder are the presence of pathological aggregates of a-synuclein into inclusions known as Lewy bodies accompanied by the loss of dopaminergic neurons in substantia nigra (5–7). Despite the fact that there is no endogenous a-synuclein in flies, Drosophila models of Parkinson’s disease have been created through transgenic expression of wild type or mutant forms of the human a-synuclein gene in flies. Gain-of-function expression of a-synuclein in the fly brain leads to Parkinson’s pathology, recapitulating several important aspects of the disease including degeneration of dopaminergic cells and formation of Lewy body-like inclusions (8, 9). These flies also show age-dependent loss of movement control. The Drosophila model of Parkinson’s disease can also be treated by some of the same drugs including dopamine agonists with positive results (10, 11). Although flies have no homologues to a-synuclein, they do have their versions of another two genes that genetically cause Parkinson’s disease—parkin and pink1. In flies, parkin appears to be downstream of pink1 in the same pathway (12, 13). Mutations in these genes lead to mitochondrial defects, muscle and locomotor dysfunction, but do not damage dopaminergic neurons (14, 15). On the other hand, overexpression of parkin in flies can suppress the effect of human a-synuclein-dependent degeneration phenotype (16). Co-overexpression of HSP70 and a-synuclein in the fly brain can rescue dopaminergic neurons against a-synuclein-induced neurodegerative phenotype (17), revealing potential therapeutic targets.

Alzheimer’s disease has also been modeled in flies. Unlike the Parkinson’s disease model, there are homologues in Drosophila to the human Alzheimer’s disease-associated genes—the amyloid precursor protein (APP) gene and Presenilin-1. Just as in humans, Presenilin (fly version) is responsible for the release of the Aß peptide from APP via proteolytic cleavage. The hallmark lesion in Alzheimer’s disease is characterized by the formation of Aß peptide-containing amyloid plaques in brain [reviewed in (18, 19)]. The mechanism of APP processing has been investigated in Drosophila using a genetic screening approach that showed Drosophila Presenilin is involved in the cleavage of the Notch protein (20). Drosophila APP appears to participate in axonal transport and if misexpressed leads to axonal vesicular accumulation (21–23). Fly models of Alzheimer’s disease have striking similarities to phenotypic defects resembling Alzheimer’s disease, in particular age-dependent learning defects, progressive neurodegeneration, and protein aggregate formation (24–28). Even more impressive is...