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Author: Ankita Sarkar
Publisher:
ISBN:
Category : Alzheimer's disease
Languages : en
Pages : 251
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Book Description
The term neurodegeneration refers to the progressive loss of neurons leading to the onset of irreversible neurodegenerative disorders like the Alzheimer's disease (AD). We have harnessed the genetics of the Drosophila melanogaster a.k.a fruit fly to elucidate the complex network of genetic and molecular mechanisms underlying neurodegeneration. We exploited the vast plethora of sophisticated genetic tools available at our disposal to mimic the neurodegenerative disease in the fly eye. Alzheimer's disease is a common form of dementia with no cure to date. One of the hallmarks of this disease is the accumulation of Amyloid plaques that triggers neuronal death. The Amyloid Precursor Protein (APP) is a trans-membrane protein which when properly cleaved forms a 40 amino acid long polypeptide but when improperly cleaved forms a 42 amino acid long polypeptide (Aß42) which is hydrophobic in nature. We believe that once these Aß42 plaques are formed they emanate certain signals that cause the healthy neurons to die. Thus it is important to identify these signals in order to delay the onset of the Aß42 mediated neurodegeneration. In order to ascertain the molecular and genetic mechanisms underlying the Aß42 mediated neurodegeneration in Alzheimer's disease several animal models have been developed. We have utilized the Drosophila eye model to understand the etiology of the disease by identifying genetic and chemical modifiers that could ameliorate the Aß42 mediated neurodegenerative phenotype. Here we discuss about one such modifier Wingless (Wg) which when downregulated or blocked rescues the Aß42 mediated neurodegeneration. A complete understanding of a disease-associated brain requires the analysis of the individual neurons. Studies till now have focused on understanding the onset of Alzheimer's disease by misexpressing the Alzheimer associated proteins in a certain group of cells with the help of the yeast derived GAL4-UAS system. In order to understand how the Aß42 plaques produced in a small group of neurons slowly spreads across the entire brain, we must understand the crosstalk between the plaque forming neurons and the surrounding healthy neurons. We thus have generated a two-clone system in order to study the fate of the surrounding wild type neurons and have seen that the Aß42 misexpressed neurons grow at the expense of the adjacent wild type neurons.
Author: Ankita Sarkar
Publisher:
ISBN:
Category : Alzheimer's disease
Languages : en
Pages : 251
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Book Description
The term neurodegeneration refers to the progressive loss of neurons leading to the onset of irreversible neurodegenerative disorders like the Alzheimer's disease (AD). We have harnessed the genetics of the Drosophila melanogaster a.k.a fruit fly to elucidate the complex network of genetic and molecular mechanisms underlying neurodegeneration. We exploited the vast plethora of sophisticated genetic tools available at our disposal to mimic the neurodegenerative disease in the fly eye. Alzheimer's disease is a common form of dementia with no cure to date. One of the hallmarks of this disease is the accumulation of Amyloid plaques that triggers neuronal death. The Amyloid Precursor Protein (APP) is a trans-membrane protein which when properly cleaved forms a 40 amino acid long polypeptide but when improperly cleaved forms a 42 amino acid long polypeptide (Aß42) which is hydrophobic in nature. We believe that once these Aß42 plaques are formed they emanate certain signals that cause the healthy neurons to die. Thus it is important to identify these signals in order to delay the onset of the Aß42 mediated neurodegeneration. In order to ascertain the molecular and genetic mechanisms underlying the Aß42 mediated neurodegeneration in Alzheimer's disease several animal models have been developed. We have utilized the Drosophila eye model to understand the etiology of the disease by identifying genetic and chemical modifiers that could ameliorate the Aß42 mediated neurodegenerative phenotype. Here we discuss about one such modifier Wingless (Wg) which when downregulated or blocked rescues the Aß42 mediated neurodegeneration. A complete understanding of a disease-associated brain requires the analysis of the individual neurons. Studies till now have focused on understanding the onset of Alzheimer's disease by misexpressing the Alzheimer associated proteins in a certain group of cells with the help of the yeast derived GAL4-UAS system. In order to understand how the Aß42 plaques produced in a small group of neurons slowly spreads across the entire brain, we must understand the crosstalk between the plaque forming neurons and the surrounding healthy neurons. We thus have generated a two-clone system in order to study the fate of the surrounding wild type neurons and have seen that the Aß42 misexpressed neurons grow at the expense of the adjacent wild type neurons.
Author: Amritpal Mudher
Publisher: Taylor & Francis
ISBN: 1000115534
Category : Science
Languages : en
Pages : 233
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Book Description
Drosophila gives an overview of the ways in which Drosophila is currently being used as a model organism to further our understanding of a spectrum of human neurological diseases. Each chapter is written by respected researchers and gives an excellent account of the subject that is suitable for postgraduate and postdoctoral researchers.
Author: Neha Gogia
Publisher:
ISBN:
Category :
Languages : en
Pages : 207
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Book Description
An important question in developmental biology is how any three-dimensional organ develops from single monolayer sheet of cells. In multicellular organisms, organogenesis requires axial patterning to determine Antero-Posterior (AP), Dorso-Ventral (DV), and Proximo-Distal (PD) axes. DV patterning marks first lineage restriction event during eye development, any deviation during this event during development results in defective organ formation. We have used Drosophila melanogaster (a.k.a, fruit fly) eye as our model organ as 75% of genetic machinery is conserved between fruit flies and humans and have identified defective proventriculus (dve, a Homeobox gene), an ortholog of SATB-homeobox-1 (special AT-rich sequence binding protein-1 in humans), as a new member of DV- patterning genes hierarchy. We have shown that (1) dve acts downstream of pannier (pnr, a GATA-1 transcription factor), and upstream of wingless (wg), (2) Loss-of-function (LOF) of both dve or pnr results in dorsal eye enlargements, while their Gain-of-function (GOF) suppresses the eye fate, and (3) Furthermore, Wingless (Wg, WNT homolog), downstream target of evolutionarily conserved Hippo growth regulatory pathway, acts downstream of dve in the eye, and exhibits similar eye enlargement or suppression phenotypes upon LOF or GOF. It suggests that like wg, dve also plays an important role in regulating growth. To characterize the function of dve (member of DV patterning pathway) during development, we looked for its interacting partners and found that it interacts antagonistically with Hippo signaling to regulate optimum levels of expression of their common downstream target, Wg, to specify eye versus head fate, during growth and patterning in developing eye. Additionally, GOF of SATB1 (vertebrate ortholog of dve) in the eye also resulted in Wg upregulation and eye suppression. Since GOF of hippo (hpo) triggers cell death, we tested if by blocking cell death by using p35 (anti-apoptotic) exhibits similar phenotypes. We found that eye enlargement phenotype resulting from GOF of hpo in dve domain, is not due to hpo mediated cell death, but by regulating retinal differentiation. Overall, this study presents a model that shows genetic interaction between two unrelated pathways of growth regulation and axial (DV) patterning and have significant bearing on developmental mechanisms. Another focus of this study is to employ Drosophila eye model to study Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disorder characterized by loss of upper and lower motor neurons in central nervous system with no known cure to-date. Mutations in genes like human-Fused in Sarcoma (h-FUS) or cabeza (caz) in Drosophila, have been known to cause ALS in flies. Misexpression of h-FUS-WT (Wild-Type), or FUS mutants FUS-R518K or FUS-R521C in Drosophila eye using GAL4-UAS genetic tool, triggers ALS-mediated neurodegeneration. To understand the mechanism of action, we screened for genetic modifiers and found hippo (hpo), as a genetic modifier. We next tested if this neuroprotective function is exclusive to hpo gene or is dependent on Hippo pathway. We modulated Hippo pathway in FUS-WT or mutant-FUS background and found that downregulation of Hippo pathway, exhibited significant rescue in the eye, but the exact mechanism of action was still unclear. Hippo pathway has been known to activate c-Jun-N-Terminal Kinase (JNK), which is involved in neurodegeneration and cell death. To elucidate the mechanism of action, we modulated JNK signaling in FUS or mutant-FUS background and found that downregulation of JNK signaling also rescued FUS mediated neurodegeneration in eye. This study presents a new model that explains how FUS causes neurodegeneration and has significant bearing on search for future therapeutic targets that can modify neurodegenerative behavior of ALS.
Author: Udai Pandey
Publisher: Frontiers Media SA
ISBN: 2832534368
Category : Science
Languages : en
Pages : 161
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Author: Meghana Tare
Publisher:
ISBN:
Category : Drosophila melanogaster
Languages : en
Pages : 240
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Book Description
Complex network of genetic and molecular mechanisms governing the process of organogenesis have an important bearing on development of organisms. We are using an established model of Drosophila melanogaster commonly referred to as fruit fly in order to understand these mechanisms. We have used Drosophila eye to discern genetic hierarchy controlling the (i) event of axial patterning, and (ii) to study neurodegeneration in the developing eye. Axial patterning involves generation of dorsal-ventral (DV), anterior-posterior (AP) and proximal-distal (PD) axes in the organ primordium and is considered crucial for transformation of monolayer epithelium into a three dimensional organ. Any abnormalities in expression patterns of axial patterning genes may result in complete loss of organ. Drosophila eye develops from a default ventral state conferred by expression of genes Lobe (L) and Serrate (Ser). It has been found that antagonistic interaction of dorsal and ventral genes helps generation of midline or the equator which is essential for growth and differentiation of the eye field. Loss-of-function of L/Ser results in complete or loss-of-ventral eye depending on time axis involved. In a genetic modifier screen performed for search for modifiers of L mutant phenotypes, an E3 ubiquitin ligase, Cullin-4 (Cul-4) and GATA-1 transcription factor Pannier (Pnr) were identified. In the current study, we have characterized Cul-4, in promoting cell survival in the ventral domain of developing eye via downregulation of Wingless (Wg) signaling. Cul-4 also regulates JNK signaling to prevent cell death in the developing eye. We thus place the Cul-4 in the hierarchy of ventral genes involved in eye development.We also present the role of GATA-1 transcription factor Pnr in defining the dorsal eye margin boundary by suppressing the eye fate. Pnr downregulates retinal determination gene machinery via zinc finger transcription factor teashirt (tsh). We thus provide a novel mechanism involved in defining dorsal margins of the eye during early stages of organogenesis and an eye suppression function, as a late role of pnr in the developing eye. Identification and characterization of these genes in the dorsal and ventral domains of the eye may help enrich our understanding of the genetic hierarchy and the complex interactions of genes involved in axial patterning in the eye during organogenesis. Since the genetic machinery is highly conserved from flies to humans, these studies will have direct implications on higher vertebrates as well. Other than patterning and growth studies, Drosophila eye has been widely used to study genetic and molecular basis of neurodegeneration. A part of current study is to test the mechanisms involved in the neuronal cell death caused during the course of Alzheimer's disease (AD). AD is caused due to accumulation of Aß-42 peptide which is a product formed because of incorrect cleavage of Amyloid Precursor Protein (APP). Accumulation of Aß-42 results in formation of amyloid plaques which eventually results into stress and the neuronal cell death. We have found that JNK signaling pathway is induced upon Aß-42 accumulation and causes cell death of the neurons in the brain. Our study provides a new mechanistic insight from the perspective of identifying the new targets of AD neuropathy.
Author: Mousumi Mutsuddi
Publisher: Springer Nature
ISBN: 981132218X
Category : Medical
Languages : en
Pages : 470
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Book Description
This book is aimed at generating an updated reservoir of scientific endeavors undertaken to unravel the complicated yet intriguing topic of neurodegeneration. Scientists from Europe, USA and India who are experts in the field of neurodegenerative diseases have contributed to this book. This book will help readers gain insight into the recent knowledge obtained from Drosophila model, in understanding the molecular mechanisms underlying neurodegenerative disorders and also unravel novel scopes for therapeutic interventions. Different methodologies available to create humanized fly models that faithfully reflects the pathogenicities associated with particular disorders have been described here. It also includes information on the exciting area of neural stem cells. A brief discussion on neurofibrillary tangles, precedes the elaborate description of lessons learnt from Drosophila about Alzheimer's, Parkinson’s, Spinomuscular Atrophy, Huntington’s diseases, RNA expansion disorders and Hereditary Spastic Paraplegia. We have concluded the book with the use of Drosophila for identifying pharmacological therapies for neurodegenerative disorders. The wide range of topics covered here will not only be relevant for beginners who are new to the concept of the extensive utility of Drosophila as a model to study human disorders; but will also be an important contribution to the scientific community, with an insight into the paradigm shift in our understanding of neurodegenerative disorders. Completed with informative tables and communicative illustrations this book will keep the readers glued and intrigued. We have comprehensively anthologized the lessons learnt on neurodegeneration from Drosophila and have thus provided an insight into the multidimensional aspects of pathogenicities of majority of the neurodegenerative disorders.
Author: Amit Singh
Publisher: Springer Nature
ISBN: 3030422461
Category : Medical
Languages : en
Pages : 368
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Book Description
Drosophila melanogaster (fruit fly) is a highly versatile model with a genetic legacy of more than a century. It provides powerful genetic, cellular, biochemical and molecular biology tools to address many questions extending from basic biology to human diseases. One of the most important questions in biology is how a multi-cellular organism develops from a single-celled embryo. The discovery of the genes responsible for pattern formation has helped refine this question and has led to other questions, such as the role of various genetic and cell biological pathways in regulating the process of pattern formation and growth during organogenesis. The Drosophila eye model has been extensively used to study molecular genetic mechanisms involved in patterning and growth. Since the genetic machinery involved in the Drosophila eye is similar to humans, it has been used to model human diseases and homology to eyes in other taxa. This updated second edition covers current progress in the study of molecular genetic mechanisms of pattern formation, mutations in axial patterning, genetic regulation of growth, and more using the Drosophila eye as a model.
Author: Prajakta Dhumraketu Deshpande
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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The goal of my Ph. D. thesis research has been to elucidate the genetic and biochemical basis of complex hereditary diseases, specifically focusing on those events that occur within the secretory pathway during protein biosynthesis. In particular, I have focused my studies on Drosophila photoreceptor cells as a model. Protein biosynthesis is a multifaceted process, involving protein folding, post-translational modifications, vesicular transport, and targeting of proteins to their correct cellular locations, to name a few. Using a collection of EMS-generated retinal degeneration mutants, I have investigated how defects in protein biosynthesis lead to neurodegenerative pathology. I have specifically focused on mechanisms of biosynthesis and trafficking of the major visual pigment in Drosophila, rhodopsin 1 (Rh1). Rh1 is a particularly good candidate for studying the constituents of protein trafficking and photoreceptor cell degeneration because of its abundance and essential role in photoreceptor cells. Therefore, I have used Rh1 as a model substrate to uncover diverse molecular signaling mechanisms that coordinate protein biosynthesis in photoreceptor cells. To date, we have identified over 300 Drosophila mutants that display defects in the expression of Rh1. Each mutant gene identified appears to adversely affect a unique step in the folding and/or vesicular transport of Rh1 in the secretory pathway. Examples include the molecular chaperones, calnexin and XPORT, required for the folding and/or transport of Rh1 (Chapter 2), the alpha-Mannosidase-IIb enzyme responsible for the deglycosylation of Rh1 (Chapter 3), the Gos28 SNARE protein involved in the vesicular transport of Rh1 (Chapter 4), and the GPI-MT2 enzyme required for photoreceptor membrane stability (Chapter 5). In all cases, the corresponding mutants undergo retinal degeneration due to defects in these highly regulated processes. In the subsequent chapters of this thesis, I provide a detailed characterization of each mutant phenotype, and describe the mechanistic role of the encoded proteins. Studies presented here will likely yield insights into the genetic and biochemical basis of protein trafficking defects in retinal degenerative disease.
Author: Kinga Maria Michno
Publisher:
ISBN:
Category :
Languages : en
Pages :
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