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Disease Models & Mechanisms

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https://www.readbyqxmd.com/read/28623239/-ccug-n-rna-toxicity-in-a-drosophila-model-for-myotonic-dystrophy-type-2-dm2-activates-apoptosis
#1
Vildan Betul Yenigun, Mario Sirito, Alla Amcheslavky, Tomek Czernuszewicz, Jordi Colonques-Bellmunt, Irma García-Alcover, Marzena Wojciechowska, Clare Bolduc, Zhihong Chen, Arturo López Castel, Ralf Krahe, Andreas Bergmann
The myotonic dystrophies are prototypic toxic RNA gain-of-function diseases. Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are caused by different unstable, noncoding microsatellite repeat expansions -- (CTG)DM1 in DMPK and (CCTG)DM2 in CNBP Although transcription of mutant repeats into (CUG)DM1 or (CCUG)DM2 appears to be necessary and sufficient to cause disease, their pathomechanisms remain incompletely understood. To study the mechanisms of (CCUG)DM2 toxicity and develop a convenient model for drug screening, we generated a transgenic DM2 model in the fruit fly Drosophila melanogaster with (CCUG)n repeats of variable length (n=16 and 106)...
June 16, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28615189/bar-coding-neurodegeneration-identifying-sub-cellular-effects-of-human-neurodegenerative-disease-proteins-using-drosophila-leg-neurons
#2
Josefin Fernius, Annika Starkenberg, Stefan Thor
Genetic, biochemical and histological studies have identified a number of different proteins as key drivers of human neurodegenerative diseases. Whereas different proteins are typically involved in different disease, there is also considerable overlap. Addressing disease protein dysfunction in an in vivo neuronal context is often time-consuming and requires labor-intensive analysis of transgenic models. To facilitate the rapid, cellular analysis of disease protein dysfunction, we have developed a fruit fly (Drosophila melanogaster) adult leg neuron assay...
June 14, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28600349/a-mouse-model-of-hereditary-coproporphyria-identified-in-an-enu-mutagenesis-screen
#3
Ashlee J Conway, Fiona C Brown, Robert O Fullinfaw, Benjamin T Kile, Stephen M Jane, David J Curtis
A genome-wide ENU mutagenesis screen in mice was performed to identify novel regulators of erythropoiesis. Here we describe a mouse line, RBC16, which harbours a dominantly inherited mutation in the Cpox gene, responsible for production of the haem biosynthesis enzyme, coproporphyrinogen III oxidase (CPOX). A premature stop codon in place of a tryptophan at amino acid 373 results in reduced mRNA expression and diminished protein levels, yielding a microcytic red cell phenotype in heterozygous mice. Urinary and faecal porphyrins in female RBC16 heterozygotes were significantly elevated compared to that of wildtype littermates, particularly coproporphyrinogen III, while males were biochemically normal...
June 9, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28600348/loss-of-the-wnt-receptor-frizzled7-in-the-gastric-epithelium-is-deleterious-and-triggers-rapid-repopulation-in-vivo
#4
Dustin J Flanagan, Nicholas Barker, Cameron Nowell, Hans Clevers, Matthias Ernst, Toby J Phesse, Elizabeth Vincan
The gastric epithelium consists of tubular glandular units each containing several differentiated cells types, and populations of stem cells, which enable the stomach to secrete the acid, mucus and various digestive enzymes required for its function. Cell signalling provides cues to regulate development and homeostasis of adult tissues, however very little is known about which cell signalling pathways are required for homeostasis of the gastric epithelium. Many diseases, such as cancer, arise as a result of deregulation to signalling pathways that regulate homeostasis of the diseased organ...
June 9, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28550101/a-novel-experimental-rat-model-of-peripheral-nerve-scarring-reliably-mimicking-post-surgical-complications-and-recurring-adhesions
#5
Angela Lemke, Carina Penzenstadler, James Ferguson, Dominika Lidinsky, Rudolf Hopf, Monika Bradl, Heinz Redl, Susanne Wolbank, Thomas Hausner
Inflammation, fibrosis and perineural adhesions with the surrounding tissue are common pathological processes following nerve injury and surgical interventions on peripheral nerves in human patients. Furthermore, these signs can reoccur following external neurolysis, currently the most common surgical treatment, thus leading to renewed nerve function impairment and chronic pain. To enable a successful evaluation of new therapeutic approaches, it is crucial to use a reproducible animal model that mimics the main clinical symptoms occurring in human patients...
May 26, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28550100/an-alternative-surgical-approach-reduces-variability-following-filament-induction-of-experimental-stroke-in-mice
#6
M Trotman-Lucas, M E Kelly, J Janus, R Fern, C L Gibson
Animal models are critical for understanding the pathology of stroke and investigating potential treatments. However, in vivo stroke models are associated, particularly in mice, with high variability in lesion volume. We investigated whether a surgical refinement where reperfusion is not reliant on the Circle of Willis reduced outcome variability. Mice underwent 60 minutes of transient middle cerebral artery occlusion avoiding ligation of the external carotid artery. During reperfusion the common carotid artery was either ligated (standard approach), or it was repaired to allow re-establishment of blood flow through the common carotid artery...
May 26, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28550099/viral-delivery-of-c9orf72-hexanucleotide-repeat-expansions-in-mice-lead-to-repeat-length-dependent-neuropathology-and-behavioral-deficits
#7
Saul Herranz-Martin, Jayanth Chandran, Katherine Lewis, Padraig Mulcahy, Adrian Higginbottom, Callum Walker, Isabel Martinez-Pena Y Valenzuela, Ross A Jones, Ian Coldicott, Tommaso Iannitti, Mohammed Akaaboune, Sherif F El-Khamisy, Thomas H Gillingwater, Pamela J Shaw, Mimoun Azzouz
Intronic GGGGCC repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two major pathologies stemming from the hexanucleotide RNA expansions (HREs) have been identified in postmortem tissue: intracellular RNA foci and repeat-associated non-ATG dependent (RAN) dipeptides, though it is unclear how these and other hallmarks of disease contribute to the pathophysiology of neuronal injury. Here we generated two novel lines of mice that overexpress either 10 pure or 102 interrupted G4C2 repeats mediated by adeno-associated virus (AAV) and characterized relevant pathology and disease-related behavioral phenotypes...
May 26, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28546289/a-tripeptidyl-peptidase-1-is-a-binding-partner-of-gphr-golgi-ph-regulator-in-dictyostelium
#8
Maria Stumpf, Rolf Müller, Berthold Gaßen, Regina Wehrstedt, Petra Fey, Malte A Karow, Ludwig Eichinger, Gernot Glöckner, Angelika A Noegel
Mutations in tripeptidyl peptidase 1 (TPP1) have been associated with late infantile neuronal ceroid lipofuscinosis (NCL2), a neurodegenerative disorder. TPP1 is a lysosomal serine protease, which removes tripeptides from the amino terminus of proteins and is composed of an N-terminal prodomain and a catalytic domain. It is conserved in mammals, amphibians, fish and the amoeba Dictyostelium discoideum. D. discoideum harbors at least six genes encoding tripeptidyl peptidase 1, tpp1A to tpp1F We identified TPP1F as binding partner of Dictyostelium GPHR (Golgi pH regulator), which is an evolutionary highly conserved intracellular transmembrane protein...
May 25, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28546288/dynamic-changes-in-the-skeletal-muscle-proteome-during-denervation-induced-atrophy
#9
Franziska Lang, Sriram Aravamudhan, Hendrik Nolte, Clara Tuerk, Soraya Hölper, Stefan Müller, Stefan Günther, Bert Blaauw, Thomas Braun, Marcus Krüger
Loss of neuronal stimulation enhances protein breakdown and reduces protein synthesis, causing rapid muscle mass loss. To elucidate the pathophysiological adaptations that occur in atrophying muscles, we used stable isotope labelling and mass spectrometry to accurately quantify protein expression changes during denervation-induced atrophy after sciatic nerve section in the mouse gastrocnemius muscle (GAST). Additionally, mice were fed a SILAC diet containing (13)C6 lysine for four, seven, or eleven days to calculate relative levels of protein synthesis in denervated and control muscles...
May 25, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28495673/parallel-imaging-of-drosophila-embryos-for-quantitative-analysis-of-genetic-perturbations-of-the-ras-pathway
#10
Yogesh Goyal, Thomas J Levario, Henry H Mattingly, Susan Holmes, Stanislav Y Shvartsman, Hang Lu
The Ras pathway patterns the poles of the Drosophila embryo by downregulating the levels and activity of a DNA-binding transcriptional repressor Capicua (Cic). We demonstrate that the spatiotemporal pattern of Cic during this signaling event can be harnessed for functional studies of the Ras-pathway mutations from human diseases. Our approach relies on a new microfluidic device that enables parallel imaging of Cic dynamics in dozens of live embryos. We found that although the pattern of Cic in early embryos is complex, it can be accurately approximated by a product of one spatial profile and one time-dependent amplitude...
May 11, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28483796/imaging-of-viral-neuroinvasion-in-the-zebrafish-reveals-that-sindbis-and-chikungunya-viruses-favour-different-entry-routes
#11
Gabriella Passoni, Christelle Langevin, Nuno Palha, Bryan C Mounce, Valérie Briolat, Pierre Affaticati, Elodie De Job, Jean-Stéphane Joly, Marco Vignuzzi, Maria-Carla Saleh, Philippe Herbomel, Pierre Boudinot, Jean-Pierre Levraud
Alphaviruses, such as chikungunya (CHIKV) and Sindbis virus (SINV), are vector‑borne pathogens that cause acute illnesses in humans and are sometimes associated with neuropathies, especially in infants and elderly patients. Little is known about their entry mechanism in the central nervous system (CNS), even for SINV, which has been used extensively as a model for viral encephalopathies. We previously established a CHIKV infection model in the optically transparent zebrafish larva; here we describe a new SINV infection model in this host...
May 8, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28450472/paneth-cell-disruption-induced-necrotizing-enterocolitis-requires-live-bacteria-and-occurs-independent-of-tlr4-signaling
#12
Jessica R White, Huiyu Gong, Brock Pope, Patrick Schlievert, Steven J McElroy
OBJECTIVE: Necrotizing enterocolitis (NEC) remains a leading cause of morbidity and mortality in premature infants. Both human surgical specimens and animal models suggest a potential involvement of Paneth cells in NEC pathogenesis. Paneth cells play critical roles in epithelial homeostasis, innate immunity, and host-microbial interactions. Yet, the complex interplay between Paneth cell disruption, epithelial barrier dysfunction, and microbial-driven inflammation remains unclear in the immature intestine...
April 27, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28424158/generation-of-a-multipurpose-prdm16-allele-by-targeted-trapping
#13
A Strassman, F Schnütgen, Q Dai, J C Jones, A C Gomez, L Pitstick, N E Holton, R Moskal, E R Leslie, H von Melchner, D R Beier, B C Bjork
Gene trap mutagenesis is a powerful tool to create loss-of-function mutations in mice and other model organisms. Modifications of traditional gene trap cassettes, including addition of conditional features in the form of Flip-excision (FlEx) arrays enabling directional gene trap cassette inversions by Cre and Flpe site-specific recombinases, greatly enhanced their experimental potential. By taking advantage of these conditional gene trap cassettes, we developed a generic strategy for generating conditional mutations and validated this strategy in mice carrying a multipurpose allele of the Prdm16 transcription factor gene...
April 19, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28389479/characterization-of-drosophila-saposin-related-mutants-as-a-model-for-lysosomal-sphingolipid-storage-diseases
#14
Julia Sellin, Heike Schulze, Marie Paradis, Dominic Gosejacob, Cyrus Papan, Andrej Shevchenko, Olympia Ekaterina Psathaki, Achim Paululat, Melanie Thielisch, Konrad Sandhoff, Michael Hoch
Sphingolipidoses are inherited diseases belonging to the class of lysosomal storage diseases (LSDs), which are characterized by the accumulation of indigestible material in the lysosome caused by specific defects in the lysosomal degradation machinery. While some LSDs can be efficiently treated by enzyme replacement therapy (ERT), this is not possible if the nervous system is affected due to the presence of the blood brain barrier. Sphingolipidoses in particular often present as severe, untreatable forms of LSDs with massive sphingolipid and membrane accumulation in lysosomes, neurodegeneration, and very short life expectancy...
April 7, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28381495/dietary-reversal-of-neuropathy-in-a-murine-model-of-prediabetes-and-the-metabolic-syndrome
#15
Lucy M Hinder, Phillipe D O'Brien, John M Hayes, Carey Backus, Andrew P Solway, Catrina Sims-Robinson, Eva L Feldman
Patients with the metabolic syndrome, defined as obesity, dyslipidemia, hypertension, and impaired glucose tolerance (IGT), can develop the same macro- and microvascular complications as patients with type 2 diabetes, including peripheral neuropathy. In type 2 diabetes, glycemic control has little effect on the development and progression of peripheral neuropathy, suggesting that other metabolic syndrome components may contribute to the presence of neuropathy. A parallel phenomenon is observed in patients with prediabetes and the metabolic syndrome, where improvement in weight and dyslipidemia more closely correlates with restoration of nerve function than improvement in glycemic status...
April 5, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28363987/progesterone-induced-neuroprotection-in-reperfusion-promoted-mitochondrial-dysfunction-following-focal-cerebral-ischemia-in-rats
#16
Syed Suhail Andrabi, Suhel Parvez, Heena Tabassum
Alterations in mitochondrial permeability transition and organelle damage are key players in the development of cerebral ischemic tissue injury due to associated modifications in ATP turnover and cellular apoptosis/necrosis. Early restoration of blood flow and improvement of mitochondrial function might reverse the situation and help in recovery following an onset of stroke. Mitochondria and related bioenergetics can be effectively used as pharmacological targets. Progesterone (P4), one of the promising neurosteroids, has been found neuroprotective in various models of neurological diseases through a number of mechanisms...
March 31, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28592657/induced-pluripotent-stem-cell-models-of-lysosomal-storage-disorders
#17
REVIEW
Daniel K Borger, Benjamin McMahon, Tamanna Roshan Lal, Jenny Serra-Vinardell, Elma Aflaki, Ellen Sidransky
Induced pluripotent stem cells (iPSCs) have provided new opportunities to explore the cell biology and pathophysiology of human diseases, and the lysosomal storage disorder research community has been quick to adopt this technology. Patient-derived iPSC models have been generated for a number of lysosomal storage disorders, including Gaucher disease, Pompe disease, Fabry disease, metachromatic leukodystrophy, the neuronal ceroid lipofuscinoses, Niemann-Pick types A and C1, and several of the mucopolysaccharidoses...
June 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28592656/hypothalamic-circuits-regulating-appetite-and-energy-homeostasis-pathways-to-obesity
#18
REVIEW
Katharina Timper, Jens C Brüning
The 'obesity epidemic' represents a major global socioeconomic burden that urgently calls for a better understanding of the underlying causes of increased weight gain and its associated metabolic comorbidities, such as type 2 diabetes mellitus and cardiovascular diseases. Improving our understanding of the cellular basis of obesity could set the stage for the development of new therapeutic strategies. The CNS plays a pivotal role in the regulation of energy and glucose homeostasis. Distinct neuronal cell populations, particularly within the arcuate nucleus of the hypothalamus, sense the nutrient status of the organism and integrate signals from peripheral hormones including pancreas-derived insulin and adipocyte-derived leptin to regulate calorie intake, glucose metabolism and energy expenditure...
June 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28325753/a-mouse-model-for-inherited-renal-fibrosis-associated-with-endoplasmic-reticulum-stress
#19
Sian E Piret, Eric Olinger, Anita A C Reed, M Andrew Nesbit, Tertius A Hough, Liz Bentley, Olivier Devuyst, Roger D Cox, Rajesh V Thakker
Renal fibrosis is a common feature of renal failure resulting from multiple etiologies, including diabetic nephropathy, hypertension and inherited renal disorders. However, the mechanisms of renal fibrosis are incompletely understood and we therefore explored these by establishing a mouse model for a renal tubular disorder, referred to as autosomal dominant tubulointerstitial kidney disease (ADTKD) due to missense uromodulin (UMOD) mutations (ADTKD-UMOD). ADTKD-UMOD, which is associated with retention of mutant uromodulin in the endoplasmic reticulum (ER) of renal thick ascending limb cells, is characterized by hyperuricemia, interstitial fibrosis, inflammation and renal failure, and we used targeted homologous recombination to generate a knock-in mouse model with an ADTKD-causing missense cysteine to arginine uromodulin mutation (C125R)...
June 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28468939/modelling-amyotrophic-lateral-sclerosis-progress-and-possibilities
#20
REVIEW
Philip Van Damme, Wim Robberecht, Ludo Van Den Bosch
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that primarily affects the motor system and presents with progressive muscle weakness. Most patients survive for only 2-5 years after disease onset, often due to failure of the respiratory muscles. ALS is a familial disease in ∼10% of patients, with the remaining 90% developing sporadic ALS. Over the past decade, major advances have been made in our understanding of the genetics and neuropathology of ALS. To date, around 20 genes are associated with ALS, with the most common causes of typical ALS associated with mutations in SOD1, TARDBP, FUS and C9orf72 Advances in our understanding of the genetic basis of ALS have led to the creation of different models of this disease...
May 1, 2017: Disease Models & Mechanisms
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