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Disease Models & Mechanisms

John P Sundberg, Paul N Schofield
The impact of the laboratory environment on animal models of human disease, particularly the mouse, has recently come under intense scrutiny regarding both the reproducibility of such environments and their ability to accurately recapitulate elements of human environmental conditions. One common objection to the use of mice in highly controlled facilities is that humans live in much more diverse and stressful environments, which affects the expression and characteristics of disease phenotypes. In this Special Article, we review some of the known effects of the laboratory environment on mouse phenotypes and compare them with environmental effects on humans that modify phenotypes or, in some cases, have driven genetic adaptation...
September 6, 2018: Disease Models & Mechanisms
S J Tunster, M Van de Pette, H D J Creeth, L Lefebvre, R M John
Beckwith-Wiedemann syndrome (BWS) is a complex imprinting disorder involving fetal overgrowth and placentomegaly and associated with a variety of genetic and epigenetic mutations affecting expression of imprinted genes on human chromosome 11p15.5. Most BWS cases are linked to loss of methylation at the Imprint Control Region 2 (ICR2) within this domain, which in mice regulates the silencing of several maternally expressed imprinted genes. Modelling this disorder in mice is confounded by the unique embryonic requirement for Ascl2 which is imprinted in mice but not humans...
August 29, 2018: Disease Models & Mechanisms
Tayeba Khan, Kerstin W Sinkevicius, Sylvia Vong, Arlen Avakian, Markley C Leavitt, Hunter Malanson, Andre Marozsan, Kim L Askew
Generalized arterial calcification of infancy (GACI) is a rare, life-threatening disorder caused by loss-of-function mutations in the gene encoding ectonucleotide pyrophosphatase phosphodiesterase 1 ( ENPP1 ), which normally hydrolyzes extracellular ATP into AMP and pyrophosphate (PPi ). The disease is characterized by extensive arterial calcification and stenosis of large- and medium- sized vessels, which leads to vascular-related complications of hypertension and heart failure. There is currently no effective treatment available, but bisphosphonates, non-hydrolyzable PPi analogs, are being used off-label to reduce arterial calcification, but there is no reported impact on the hypertension and cardiac dysfunction features of GACI...
August 29, 2018: Disease Models & Mechanisms
Zaid Tanvir, Ralph F Nelson, Kathleen DeCicco-Skinner, Victoria P Connaughton
Prolonged hyperglycemia can alter retinal function ultimately resulting in blindness. Zebrafish adults exposed to alternating 2% glucose conditions display a 3x increase in blood sugar levels. After 4 weeks of treatment, electroretinograms (ERGs) were recorded from isolated, perfused, in vitro eyecups. Control animals were exposed either to alternating 2% mannitol (osmotic control) or alternating water (handling control). Two types of ERGs were recorded: (1) native ERGs measured using white light stimuli and media without synaptic blockers and (2) spectral ERGs measured with an AMPA/KA antagonist, isolating photoreceptor-to-ON-bipolar cell synapses, and a spectral protocol that separated R, G, B, and UV cone signals...
August 29, 2018: Disease Models & Mechanisms
Thu Lan Nguyen, Arnaud Duchon, Antigoni Manousopoulou, Nadège Loaëc, Benoît Villiers, Guillaume Pani, Meltem Karatas, Anna E Mechling, Laura-Adela Harsan, Emmanuelle Limanton, Jean-Pierre Bazureau, François Carreaux, Spiros D Garbis, Laurent Meijer, Yann Herault
Growing evidence support the implication of DYRK1A in the development of cognitive deficits seen in Down syndrome (DS) and Alzheimer's disease (AD). We here demonstrate that pharmacological inhibition of brain DYRK1A is able to correct recognition memory deficits in three DS mouse models with increasing genetic complexity (Tg( Dyrk1a ), Ts65Dn, Dp1Yey), all expressing an extra copy of Dyrk1a Overexpressed DYRK1A accumulates in the cytoplasm and at the synapse. Treatment of the three DS models with the pharmacological DYRK1A inhibitor Leucettine L41 leads to normalization of DYRK1A activity and corrects the novel object cognitive impairment observed in these models...
August 16, 2018: Disease Models & Mechanisms
Amram Torgeman, Arieh Schwartz, Eran Diamant, Tzadok Baruchi, Eyal Dor, Alon Ben David, Avi Pass, Ada Barnea, Arnon Tal, Amir Rosner, Osnat Rosen, Ran Zichel
Botulinum neurotoxin (BoNT) serotypes A, B and E are responsible for most cases of human botulism. The only approved therapy for botulism is antitoxin treatment administered to patients after symptom onset. However, a recent meta-analysis of antitoxin efficacy in human botulism cases over the last century concluded that a statistically significant reduction in mortality is associated with the use of type-E and type-A but not type-B antitoxin. Animal models could be highly valuable in studying post-symptom antitoxin efficacy (PSAE)...
August 16, 2018: Disease Models & Mechanisms
Hongde Li, Alexander J Hurlburt, Jason M Tennessen
The enantiomers of 2-hydroxyglutarate (2HG) are potent regulators of metabolism, chromatin modifications, and cell fate decisions. Although these compounds are associated with tumor metabolism and commonly referred to as oncometabolites, both D- and L-2HG are also synthesized by healthy cells and likely serve endogenous functions. The metabolic mechanisms that control 2HG metabolism in vivo , however, remain poorly understood. One clue towards how cells regulate 2HG levels has emerged from an inborn error of metabolism known as combined D- and L-2HG aciduria (D-/L-2HGA), which results in elevated D- and L-2HG accumulation...
August 14, 2018: Disease Models & Mechanisms
Eunate Gallardo-Vara, Simon Tual-Chalot, Luisa M Botella, Helen M Arthur, Carmelo Bernabeu
Endoglin is a transmembrane glycoprotein expressed in vascular endothelium that plays a key role in angiogenesis. Mutations in the endoglin gene (ENG) cause Hereditary Hemorrhagic Telangiectasia type 1 (HHT1), characterized by arteriovenous malformations (AVMs) in different organs. These vascular lesions derive from abnormal processes of angiogenesis where aberrant vascular remodeling leads to focal loss of capillaries. Current treatments for HHT1 include anti-angiogenic therapies. Interestingly, a circulating form of endoglin (also known as soluble endoglin, sEng), proteolytically released from the membrane-bound protein and displaying anti-angiogenic activity, has been described in several endothelial-related pathological conditions...
August 14, 2018: Disease Models & Mechanisms
Sohrab N Ali, Thamara K Dayarathna, Aymon N Ali, Tijani Osumah, Mohamed Ahmed, Tyler T Cooper, Nicholas E Power, Dongxing Zhang, Dajung Kim, Rachel Kim, Andre St Amant, Jinqiang Hou, Thomas Tailly, Jun Yang, Len Luyt, Paul A Spagnuolo, Jeremy P Burton, Hassan Razvi, Hon S Leong
Kidney stone disease involves the aggregation of stone-forming salts consequent to solute supersaturation in urine. The development of novel therapeutic agents for this predominantly metabolic and biochemical disorder have been hampered by the lack of a practical pre-clinical model amenable to drug screening. Here, Drosophila melanogaster , an emerging model for kidney stone disease research, was adapted as a high throughput functional drug screening platform agnostic of the multifactorial nature of mammalian nephrolithiasis...
August 6, 2018: Disease Models & Mechanisms
Scott J Callahan, Stephanie Tepan, Yan M Zhang, Helen Lindsay, Alexa Burger, Nathaniel R Campbell, Isabella S Kim, Travis J Hollmann, Lorenz Studer, Christian Mosimann, Richard M White
Transgenic animals are invaluable for modeling cancer genomics, but often require complex crosses of multiple germline alleles to obtain the desired combinations. Zebrafish models have advantages in that transgenes can be rapidly tested by mosaic expression, but these typically lack spatial and temporal control of tumor onset, which limits their utility for the study of tumor progression and metastasis. To overcome these limitations, we have developed a method called Transgene Electroporation in Adult Zebrafish (TEAZ)...
July 30, 2018: Disease Models & Mechanisms
Patrick D Olson, Lisa K McLellan, Alice Liu, Kelleigh E Briden, Kristin M Tiemann, Allyssa L Daugherty, Keith A Hruska, David A Hunstad
No abstract text is available yet for this article.
September 13, 2018: Disease Models & Mechanisms
Lin Song, Ramesh Rijal, Malte Karow, Maria Stumpf, Oliver Hahn, Laura Park, Robert Insall, Rolf Schröder, Andreas Hofmann, Christoph S Clemen, Ludwig Eichinger
Hereditary spastic paraplegias (HSPs) are genetically diverse and clinically characterised by lower limb weakness and spasticity. The N471D and several other point mutations of human strumpellin (Str; also known as WASHC5), a member of the Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complex, have been shown to cause a form of HSP known as spastic paraplegia 8 (SPG8). To investigate the molecular functions of wild-type (WT) and N417D Str, we generated Dictyostelium Str- cells and ectopically expressed StrWT -GFP or StrN471D -GFP in Str- and WT cells...
September 13, 2018: Disease Models & Mechanisms
Clément Plaud, Vandana Joshi, Natallie Kajevu, Christian Poüs, Patrick A Curmi, Andrea Burgo
Mutations of the SPG4 ( SPAST ) gene encoding for spastin protein are the main causes of hereditary spastic paraplegia. Spastin binds to microtubules and severs them through the enzymatic activity of its AAA domain. Several missense mutations located in this domain lead to stable, nonsevering spastins that decorate a subset of microtubules, suggesting a possible negative gain-of-function mechanism for these mutants. Of the two main isoforms of spastin, only mutations of the long isoform, M1, are supposed to be involved in the onset of the pathology, leaving the role of the ubiquitously expressed shorter one, M87, not fully investigated and understood...
September 10, 2018: Disease Models & Mechanisms
Román Darío Moreno-Fernández, Andrea Nieto-Quero, Francisco Javier Gómez-Salas, Jerold Chun, Guillermo Estivill-Torrús, Fernando Rodríguez de Fonseca, Luis Javier Santín, Margarita Pérez-Martín, Carmen Pedraza
Animal models of psychopathology are particularly useful for studying the neurobiology of depression and characterising the subtypes. Recently, our group was the first to identify a possible relationship between the LPA1 receptor and a mixed anxiety-depression phenotype. Specifically, maLPA1 -null mice exhibited a phenotype characterised by depressive and anxious features. However, the constitutive lack of the gene encoding the LPA1 receptor ( Lpar1 ) can induce compensatory mechanisms that might have resulted in the observed deficits...
September 10, 2018: Disease Models & Mechanisms
Hong Zhang, Alexey V Dvornikov, Inken G Huttner, Xiao Ma, Celine F Santiago, Diane Fatkin, Xiaolei Xu
Zebrafish are increasingly used as a vertebrate model to study human cardiovascular disorders. Although heart structure and function are readily visualized in zebrafish embryos because of their optical transparency, the lack of effective tools for evaluating the hearts of older, nontransparent fish has been a major limiting factor. The recent development of high-frequency echocardiography has been an important advance for in vivo cardiac assessment, but it necessitates anesthesia and has limited ability to study acute interventions...
September 10, 2018: Disease Models & Mechanisms
Katharina Dannhausen, Christoph Möhle, Thomas Langmann
Juvenile neuronal ceroid lipofuscinosis (jNCL) is a rare but fatal inherited lysosomal storage disorder mainly affecting children. The disease is caused by mutations in the CLN3 gene that lead to the accumulation of storage material in many tissues, prominent immune responses and neuronal degeneration. One of the first symptoms is vision loss followed by motor dysfunction and mental decline. The established Cln3Δex7/8 mouse model mimics many pathological features of the human disease except the retinal phenotype, which is very mild and occurs only very late in these mice...
September 5, 2018: Disease Models & Mechanisms
Joseph Burclaff, Jason C Mills
Recent studies have identified and begun to characterize the roles of regenerative cellular plasticity in many organs. In Part I of our two-part Review, we discussed how cells reprogram following injury to the stomach and pancreas. We introduced the concept of a conserved cellular program, much like those governing division and death, which may allow mature cells to become regenerative. This program, paligenosis, is likely necessary to help organs repair the numerous injuries they face over the lifetime of an organism; however, we also postulated that rounds of paligenosis and redifferentiation may allow long-lived cells to accumulate and store oncogenic mutations, and could thereby contribute to tumorigenesis...
August 31, 2018: Disease Models & Mechanisms
Jens Tiefenbach, Lilia Magomedova, Jiabao Liu, Arkadiy A Reunov, Ricky Tsai, Neena S Eappen, Rebecca A Jockusch, Corey Nislow, Carolyn L Cummins, Henry M Krause
Current peroxisome proliferator-activated receptor (PPAR)-targeted drugs, such as the PPARγ-directed diabetes drug rosiglitazone, are associated with undesirable side effects due to robust agonist activity in non-target tissues. To find new PPAR ligands with fewer toxic effects, we generated transgenic zebrafish that can be screened in high throughput for new tissue-selective PPAR partial agonists. A structural analog of coenzyme Q10 (idebenone) that elicits spatially restricted partial agonist activity for both PPARα and PPARγ was identified...
August 31, 2018: Disease Models & Mechanisms
Elise L Donovan, Erika Barboza Prado Lopes, Albert Batushansky, Mike Kinter, Timothy M Griffin
Obesity is one of the most significant risk factors for knee osteoarthritis. However, therapeutic strategies to prevent or treat obesity-associated osteoarthritis are limited because of uncertainty about the etiology of disease, particularly with regard to metabolic factors. High-fat-diet-induced obese mice have become a widely used model for testing hypotheses about how obesity increases the risk of osteoarthritis, but progress has been limited by variation in disease severity, with some reports concluding that dietary treatment alone is insufficient to induce osteoarthritis in mice...
August 31, 2018: Disease Models & Mechanisms
Luna Simona Pane, Filomena Gabriella Fulcoli, Andrea Cirino, Alessandra Altomonte, Rosa Ferrentino, Marchesa Bilio, Antonio Baldini
The TBX1 gene is haploinsufficient in 22q11.2 deletion syndrome (22q11.2DS), and genetic evidence from human patients and mouse models points to a major role of this gene in the pathogenesis of this syndrome. Tbx1 can activate and repress transcription, and previous work has shown that one of its functions is to negatively modulate cardiomyocyte differentiation. Tbx1 occupies the anterior heart field (AHF) enhancer of the Mef2c gene, which encodes a key cardiac differentiation transcription factor. Here, we show that increased dosage of Tbx1 correlates with downregulation of Mef2c expression and reduced acetylation of its AHF enhancer in cultured mouse myoblasts...
August 30, 2018: Disease Models & Mechanisms
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