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Disease Models & Mechanisms

Chris P Ponting
A single change in DNA, RNA, proteins or cellular images can be useful as a biomarker of disease onset or progression. With high-throughput molecular phenotyping of single cells, it is now conceivable that the molecular changes occurring across thousands, or tens of thousands, of individual cells could additionally be considered as a disease biomarker. Transition to a disease state would then be reflected by the shifts in cell numbers and locations across a multidimensional space that is defined by the molecular content of cells...
January 14, 2019: Disease Models & Mechanisms
Wendell Jones, Juan Rodriguez, Steven Bassnett
Fibrillin is an evolutionarily ancient protein that lends elasticity and resiliency to a variety of tissues. In humans, mutations in fibrillin-1 cause Marfan and related syndromes, conditions in which the eye is often severely affected. To gain insights into the ocular sequelae of Marfan syndrome, we targeted Fbn1 in mouse lens or non-pigmented ciliary epithelium (NPCE). Conditional knockout of Fbn1 in NPCE, but not lens, profoundly affected the ciliary zonule, the system of fibrillin-rich fibers that centers the lens in the eye...
January 14, 2019: Disease Models & Mechanisms
A R Lopez-Pastor, A Gomez-Hernandez, S Diaz-Castroverde, G Gonzalez-Aseguinolaza, A Gonzalez-Rodriguez, G Garcia, S Fernandez, O Escribano, M Benito
One of the main complications associated to obesity is insulin resistance and an altered glucose and lipid metabolism within the liver. It has been previously described that insulin receptor isoform A (IRA) favors glucose uptake and glycogen storage in hepatocytes as compared to isoform B (IRB) improving glucose homeostasis in mice lacking liver insulin receptor. Thus, we hypothesized that IRA could also improve glucose and lipid metabolism in a mouse model of high fat diet-induced obesity. We addressed the role of insulin receptor isoforms on glucose and lipid metabolism in vivo We expressed IRA or IRB specifically in the liver by using adeno-associated viruses (AAV) in a mouse model of diet-induced insulin resistance and obesity...
January 14, 2019: Disease Models & Mechanisms
Kriti Chaplot, Lokesh Pimpale, Balaji Ramalingam, Senthilkumar Deivasigamani, Siddhesh S Kamat, Girish S Ratnaparkhi
Familial Amyotrophic Lateral Sclerosis (F-ALS) is an incurable, late onset motor neuron disease, linked strongly to various causative genetic loci. ALS8 codes for a missense mutation, P56S, in VAMP-associated Protein B (VAPB) that causes the protein to misfold and form cellular aggregates. Uncovering genes and mechanisms that affect aggregation dynamics would greatly help increase our understanding of the disease and lead to potential therapeutics.We developed a quantitative high-throughput, Drosophila S2R+ cell-based kinetic assay coupled with fluorescent microscopy to score for genes involved in the modulation of aggregates of fly ortholog, VAP(P58S), fused with GFP...
January 11, 2019: Disease Models & Mechanisms
Piotr Soczewka, Damian Kolakowski, Iwona Smaczynska-de Rooij, Weronika Rzepnikowska, Kathryn R Ayscough, Joanna Kaminska, Teresa Zoladek
Chorea-acanthocytosis (ChAc) is a rare neurodegenerative disease associated with mutations in the human VPS13A gene. The mechanism of ChAc pathogenesis is unclear. A simple yeast model was used to investigate the function of Vps13. Vps13, like hVps13A, is involved in vesicular protein transport, actin cytoskeleton organisation and phospholipid metabolism. A new phenotype of the vps13 Δ mutant, SDS-hypersensitivity, was used to screen a yeast genomic library for multicopy suppressors. A fragment of the MYO3 gene, encoding the N-terminal part of myosin, a protein involved in the actin cytoskeleton and in endocytosis, was isolated...
January 11, 2019: Disease Models & Mechanisms
Kelsey F Sugrue, Anjali A Sarkar, Linda Leatherbury, Irene E Zohn
The development of the aortic arch is a complex process that involves remodeling of the bilaterally symmetrical pharyngeal arch arteries (PAAs) into the mature asymmetric aortic arch. Retinoic acid signaling is a key regulator of this process by directing patterning of the second heart field (SHF), formation of the caudal PAAs and subsequent remodeling of the PAAs to form the aortic arch. Here we identify the HECTD1 ubiquitin ligase as a novel modulator of retinoic acid signaling during this process. Hectd1 opm/opm homozygous mutant embryos show a spectrum of aortic arch abnormalities that occur following loss of 4th PAAs and increased SHF marker expression...
December 21, 2018: Disease Models & Mechanisms
Martina Marinello, Andreas Werner, Mariagiovanna Giannone, Khadija Tahiri, Sandro Alves, Christelle Tesson, Wilfred den Dunnen, Jacob-S Seeler, Alexis Brice, Annie Sittler
Perturbation of protein homeostasis and aggregation of misfolded proteins is a major cause of many human diseases. A hallmark of the neurodegerative disease spinocerebellar ataxia type 7 (SCA7) is given by the intranuclear accumulation of mutant, misfolded ataxin-7 (polyQ-ATXN7). Here we show that endogenous ATXN7 is modified by SUMO, thus also suggesting a physiological role for this modification under conditions of proteotoxic stress caused by the accumulation of misfolded ATXN7. Co-immunoprecipitation experiments, immunofluorescence microscopy and proximity ligation assays confirmed co-localization and interaction of polyQ-ATXN7 with SUMO2 in cells...
December 17, 2018: Disease Models & Mechanisms
Divya Krishnamoorthy, Robert C Hoy, Devorah M Natelson, Olivia M Torre, Damien M Laudier, James C Iatridis, Svenja Illien-Jünger
Back pain is a leading cause of disability strongly associated with intervertebral disc (IVD) degeneration. Reducing structural disruption and catabolism in IVD degeneration remains an important clinical challenge. Pro-oxidant and structure-modifying advanced glycation end-products (AGEs) contribute to obesity and diabetes, which are associated with increased back pain, and accumulate in tissues due to hyperglycemia or ingestion of foods processed at high heat. Collagen-rich IVDs are particularly susceptible to AGE accumulation due to their slow metabolic rates yet it is unclear if dietary AGEs can cross the endplates to accumulate in IVDs...
November 29, 2018: Disease Models & Mechanisms
Amy S Findlay, Roderick N Carter, Becky Starbuck, Lisa McKie, Klára Nováková, Peter S Budd, Margaret A Keighren, Joseph A Marsh, Sally H Cross, Michelle M Simon, Paul K Potter, Nicholas M Morton, Ian J Jackson
Isocitrate dehydrogenase (IDH) is an enzyme required for the production of α-ketoglutarate from isocitrate. IDH3 generates the NADH used in the mitochondria for ATP production, and is a tetramer made up of two α, a β and a γ subunit. Loss of function and missense mutations in both IDH3A and IDH3B have previously been implicated in families exhibiting retinal degeneration. Using mouse models we have investigated the role of IDH3 in retinal disease and mitochondrial function.We identified mice with late-onset retinal degeneration in a screen of ageing mice carrying an ENU-induced mutation, E229K, in Idh3a Mice homozygous for this mutation exhibit signs of retinal stress, indicated by GFAP staining, as early as 3 months, but no other tissues appear to be affected...
November 26, 2018: Disease Models & Mechanisms
Bao-Luen Chang, Marco Leite, Albert Snowball, Andreas Lieb, Elodie Chabrol, Matthew C Walker, Dimitri M Kullmann, Stephanie Schorge, Robert C Wykes
Focal neocortical epilepsy is a common form of epilepsy and there is a need to develop animal models that allow the evaluation of novel therapeutic strategies to treat this type of epilepsy. Tetanus toxin (TeNT) injection into rat visual cortex induces focal neocortical epilepsy without preceding status epilepticus. The latency to first seizure ranged from 3 to 7 days. Seizure duration was bimodal, with both short (approximately 30s) and long-lasting (>100s) seizures occurring in the same animals. Seizures were accompanied by non-motor features such as behavioural arrest, or motor seizures with or without evolution to generalized tonic-clonic seizures...
November 22, 2018: Disease Models & Mechanisms
Brian Chipman Belyea, Fang Xu, Maria Luisa Soledad Sequeira-Lopez, Roberto Ariel Gomez
Conditional deletion of RBP-J , the major transcriptional effector of Notch signaling, specifically within renin-expressing cells leads to the development of B cell leukemia. However, the influence of contributing factors such as mouse strain, cell of origin, and cre recombinase copy number are unknown. In this study, we compared RBP-J deletion efficiency using 1 versus 2 copies of cre recombinase. Further, we compared the incidence and timing of leukemia development in two unique strains of mice, C57BL/6 and 129/Sv, as well as at different B cell developmental stages...
November 22, 2018: Disease Models & Mechanisms
Phillipe D O'Brien, Lucy M Hinder, Amy E Rumora, John M Hayes, Jacqueline R Dauch, Carey Backus, Faye E Mendelson, Eva L Feldman
Peripheral neuropathy (neuropathy) is a common complication of obesity and type 2 diabetes in children and adolescents. To model this complication in mice, 5-week old male C57BL/6J mice were fed a high-fat diet to induce diet-induced obesity (DIO), a model of prediabetes, and a cohort of these animals was injected with low-dose streptozotocin (STZ) at 12 weeks of age to induce hyperglycemia and type 2 diabetes. Neuropathy assessments at 16, 24, and 36 weeks demonstrated that DIO and DIO-STZ mice displayed decreased motor and sensory nerve conduction velocities as early as 16 weeks, hypoalgesia by 24 weeks, and cutaneous nerve fiber loss by 36 weeks, relative to control mice fed a standard diet...
November 16, 2018: Disease Models & Mechanisms
Maria R Replogle, Virinchipuram S Sreevidya, Vivian M Lee, Michael D Laiosa, Kurt R Svoboda, Ava J Udvadia
The neural crest (NC) is a transient population of embryonic progenitors that are implicated in a diverse range of congenital birth defects and pediatric syndromes. The broad spectrum of NC-related disorders can be attributed to the wide variety of differentiated cell types arising from the NC. In vitro models of NC development provide a powerful platform for testing the relative contributions of intrinsic and extrinsic factors mediating NC differentiation under normal and pathogenic conditions. Although differentiation is a dynamic process that unfolds over time, currently, there is no well-defined chronology that characterizes the in vitro progression of NC differentiation towards specific cell fates...
November 8, 2018: Disease Models & Mechanisms
Jennifer E Hewitt, Amelia K Pollard, Leila Lesanpezeshki, Colleen S Deane, Christopher J Gaffney, Timothy Etheridge, Nathaniel J Szewczyk, Siva A Vanapalli
Muscle strength is a key clinical parameter used to monitor the progression of human muscular dystrophies including Duchenne and Becker muscular dystrophies. Although Caenorhabditis elegans is an established genetic model for studying mechanisms and treatments of muscular dystrophies, analogous strength-based measurements in this disease model are lacking. Here we describe the first demonstration of the direct measurement of muscular strength in dystrophin-deficient C. elegans mutants using a micropillar-based force measurement system called NemaFlex...
November 5, 2018: Disease Models & Mechanisms
Chana Yagil, Ronen Varadi-Levi, Yoram Yagil
The mechanisms underlying diabetes remain unresolved. The Cohen Diabetic rat represents a model of diet-induced diabetes in which the disease is induced after exposure to a diabetogenic diet (DD) in the diabetes sensitive (CDs/y) but not in the resistant (CDr/y) strain. Diet imposes a metabolic strain that leads to diabetes in the appropriate genetic background. We previously identified through whole genome linkage analysis a diabetes-related QTL on RNO4 which incorporates NADH dehydrogenase (ubiquinone) 1 alpha sub-complex 4 ( Ndufa4 ), a nuclear gene that affects mitochondrial function...
October 25, 2018: Disease Models & Mechanisms
Troy A McDiarmid, Vinci Au, Aaron D Loewen, Joseph Liang, Kota Mizumoto, Donald G Moerman, Catharine H Rankin
Our ability to sequence genomes has vastly surpassed our ability to interpret the genetic variation we discover. This presents a major challenge in the clinical setting, where the recent application of whole exome and whole genome sequencing has uncovered thousands of genetic variants of uncertain significance. Here, we present a strategy for targeted human gene replacement and phenomic characterization based on CRISPR-Cas9 genome engineering in the genetic model organism Caenorhabditis elegans that will facilitate assessment of the functional conservation of human genes and structure-function analysis of disease-associated variants with unprecedented precision...
October 25, 2018: Disease Models & Mechanisms
Channabasavaiah B Gurumurthy, Kevin C Kent Lloyd
Over the past decade, new methods and procedures have been developed to generate genetically engineered mouse models of human disease. This At a Glance article highlights several recent technical advances in mouse genome manipulation that have transformed our ability to manipulate and study gene expression in the mouse. We discuss how conventional gene targeting by homologous recombination in embryonic stem cells has given way to more refined methods that enable allele-specific manipulation in zygotes. We also highlight advances in the use of programmable endonucleases that have greatly increased the feasibility and ease of editing the mouse genome...
January 8, 2019: Disease Models & Mechanisms
Francesca De Giorgio, Cheryl Maduro, Elizabeth M C Fisher, Abraham Acevedo-Arozena
A wide range of genetic mouse models is available to help researchers dissect human disease mechanisms. Each type of model has its own distinctive characteristics arising from the nature of the introduced mutation, as well as from the specific changes to the gene of interest. Here, we review the current range of mouse models with mutations in genes causative for the human neurodegenerative disease amyotrophic lateral sclerosis. We focus on the two main types of available mutants: transgenic mice and those that express mutant genes at physiological levels from gene targeting or from chemical mutagenesis...
January 2, 2019: Disease Models & Mechanisms
Alec R Nickolls, Carsten G Bönnemann
Dystroglycan is a cell membrane protein that binds to the extracellular matrix in a variety of mammalian tissues. The α-subunit of dystroglycan (αDG) is heavily glycosylated, including a special O-mannosyl glycoepitope, relying upon this unique glycosylation to bind its matrix ligands. A distinct group of muscular dystrophies results from specific hypoglycosylation of αDG, and they are frequently associated with central nervous system involvement, ranging from profound brain malformation to intellectual disability without evident morphological defects...
December 19, 2018: Disease Models & Mechanisms
Emre E Turer, Miguel San Miguel, Kuan-Wen Wang, William McAlpine, Feiya Ou, Xiaohong Li, Miao Tang, Zhao Zang, Jianhui Wang, Braden Hayse, Bret Evers, Xiaoming Zhan, Jamie Russell, Bruce Beutler
Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) is a member of the basic helix-loop-helix/PER-ARNT-SIM (bHLH/PAS) transcription factor family. ARNT2 heterodimerizes with several members of the family, including single-minded homolog-1 (SIM1) and neuronal PAS domain protein 4 (NPAS4), primarily in neurons of the central nervous system. We screened 64,424 third-generation germline mutant mice derived from N -ethyl- N -nitrosourea (ENU)-mutagenized great-grandsires for weight abnormalities. Among 17 elevated body weight phenotypes identified and mapped, one strongly correlated with an induced missense mutation in Arnt2 using a semidominant model of inheritance...
December 18, 2018: Disease Models & Mechanisms
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