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Disease Models & Mechanisms

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https://www.readbyqxmd.com/read/28819044/the-parkinson-s-disease-associated-protein-dj-1-plays-a-positive-nonmitochondrial-role-in-endocytosis-in-dictyostelium-cells
#1
Suwei Chen, Sarah J Annesley, Rasha A F Jasim, Vanessa J Musco, Oana Sanislav, Paul R Fisher
The loss of function of DJ-1 caused by mutations of DJ-1 causes a form of familial Parkinson's Disease (PD). However, the role of DJ-1 in healthy and in PD cells is poorly understood. Even its subcellular localization in mammalian cells is uncertain, both cytosolic and mitochondrial locations having been reported. We show here that DJ-1 is normally located in the cytoplasm in healthy Dictyostelium discoideum cells. With its unique life cycle, straightforward genotype-phenotype relationships, experimental accesibility and genetic tractability, Dictyostelium discoideum offers an attractive model to investigate the roles of PD-associated genes...
August 17, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28819043/increased-acetylation-of-microtubules-rescues-human-tau-induced-microtubule-defects-and-neuromuscular-junction-abnormalities-in-drosophila
#2
Chuan-Xi Mao, Xue Wen, Shan Jin, Yong Q Zhang
Tau normally associates with and stabilizes microtubules (MTs), but is hyperphosphorylated and aggregated into neurofibrillary tangles in Alzheimer's disease and related neurodegenerative diseases, which are collectively known as tauopathies. MTs are regulated by different forms of post-translational modification including acetylation; acetylated MTs represent a more stable microtubule population. In our previous study, we show that inhibition of histone deacetylase 6 (HDAC6), which deacetylates tubulin at lysine 40, rescues defects in MTs and in neuromuscular junction growth caused by tau overexpression...
August 17, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28801532/activation-of-nkx2-5-calr-p53-signaling-pathway-by-hyperglycemia-induces-cardiac-remodeling-and-dysfunction-in-adult-zebrafish
#3
Sun Yanyi, Wang Qiuyun, Fang Yuehua, Wu Chunfang, Lu Guoping, Chen Zhenyue
Hyperglycemia is an independent risk factor for diabetic cardiomyopathy in humans; however, the underlying mechanisms have not been thoroughly elucidated. Zebrafish (Danio rerio) was used in this study as a novel vertebrate model to explore the signaling pathways of human adult cardiomyopathy. Hyperglycemia was induced by alternately immersing adult zebrafish in a glucose solution or water. The hyperglycemic fish gradually exhibited some hallmarks of cardiomyopathy such as myocardial hypertrophy and apoptosis, myofibril loss, fetal gene reactivation, and severe arrhythmia...
August 11, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28798136/adipose-tissue-metabolic-and-inflammatory-responses-to-stroke-are-altered-in-obese-mice
#4
Michael J Haley, Graham Mullard, Katherine A Hollywood, Garth J Cooper, Warwick B Dunn, Catherine B Lawrence
Obesity is an independent risk factor for stroke, though several clinical studies have reported that obesity improves stroke outcome. Obesity is hypothesised to aid recovery by protecting against post-stroke catabolism. We therefore assessed whether obese mice had an altered metabolic and inflammatory response to stroke. Obese ob/ob mice underwent 20 min middle cerebral artery occlusion and 24 h reperfusion. Lipid metabolism and expression of inflammatory cytokines were assessed in the plasma, liver and adipose tissue...
August 10, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28768697/a-novel-high-throughput-yeast-genetic-screen-for-factors-modifying-protein-levels-of-the-early-onset-torsion-dystonia-associated-variant-torsina%C3%AE-e
#5
Lucía F Zacchi, John C Dittmar, Michael J Mihalevic, Annette M Shewan, Benjamin L Schulz, Jeffrey L Brodsky, Kara A Bernstein
Dystonia is the third most common movement disorder, but its diagnosis and treatment remain challenging. One of the most severe types of Dystonia is Early-Onset Torsion Dystonia (EOTD). The best studied and validated EOTD-associated mutation, torsinAΔE, is a deletion of a C-terminal glutamate residue in the AAA+ ATPase, torsinA. TorsinA appears to be an Endoplasmic Reticulum (ER)/Nuclear Envelope chaperone with multiple roles in the secretory pathway and in determining subcellular architecture. Many functions are disabled in the torsinAΔE variant, and torsinAΔE is also less stable than wild-type torsinA and is a substrate for ER-associated degradation...
August 2, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28754838/the-chromatin-remodeling-bap-complex-limits-tumor-promoting-activity-of-the-hippo-pathway-effector-yki-to-prevent-neoplastic-transformation-in-drosophila-epithelia
#6
Shilin Song, Héctor Herranz, Stephen M Cohen
SWI/SNF chromatin remodeling complexes are mutated in many human cancers. In this report we make use of a Drosophila genetic model for epithelial tumor formation to explore the tumor suppressive role of SWI/SNF complex proteins. Members of the BAP complex exhibit tumor suppressor activity in tissue overexpressing the Yorkie (Yki) proto-oncogene, but not in tissue overexpressing EGFR. The BAP complex has been reported to serve as a Yki-binding cofactor to support Yki target expression. However, we observed that depletion of BAP leads to ectopic expression of Yki targets both autonomously and non-autonomously, suggesting additional indirect effects...
July 28, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28754837/p53-independent-dux4-pathology
#7
Darko Bosnakovski, Micah D Gearhart, Erik A Toso, Olivia O Recht, Anja Cucak, Abhinav K Jain, Michelle C Barton, Michael Kyba
FSHD is a genetically dominant myopathy caused by mutations that disrupt repression of the normally silent DUX4 gene, which encodes a transcription factor that has been shown to interfere with myogenesis when misexpressed at very low levels in myoblasts, and to cause cell death when overexpressed at high levels. A previous report using adeno-associated virus to deliver high levels of DUX4 to mouse skeletal muscle demonstrated severe pathology that was suppressed on a p53 knockout background, implying that DUX4 acted through the p53 pathway...
July 28, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28754836/screening-in-larval-zebrafish-reveals-tissue-specific-distributions-of-fifteen-fluorescent-compounds
#8
Yuxiao Yao, Shaoyang Sun, Fei Fei, Jingjing Wang, Youhua Wang, Ranran Zhang, Jing Wu, Lian Liu, Xiuyun Liu, Zhaomeng Cui, Qiang Li, Min Yu, Yongjun Dang, Xu Wang
Zebrafish is a prominent vertebrate model for low cost in vivo whole organism screening. In our recent screening of the distribution patterns of fluorescent compounds in live zebrafish larvae, fifteen compounds with tissue-specific distributions were identified. Several compounds were observed to accumulate in tissues where they were reported to induce side effects, and compounds with similar structures tended to be enriched in the same tissues, with minor differences. In particular, we found three novel red fluorescent bone staining dyes: purpurin, lucidin and 3-hydroxy-morindone, among which purpurin can effectively label bones in both larval and adult zebrafish, as well as in postnatal mice, without significantly affecting bone mass and density...
July 28, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28733363/lipidomic-profiling-of-patient-specific-induced-pluripotent-stem-cell-derived-hepatocyte-like-cells
#9
Mostafa Kiamehr, Leena E Viiri, Terhi Vihervaara, Kaisa M Koistinen, Mika Hilvo, Kim Ekroos, Reijo Käkelä, Katriina Aalto-Setälä
Hepatocyte-like cells (HLCs) differentiated from human induced pluripotent stem cells (iPSCs) offer an alternative model for primary human hepatocytes to study lipid aberrations. However, the detailed lipid profile of HLCs is yet unknown. In the current study, functional HLCs were differentiated from iPSCs generated from dermal fibroblasts of three individuals by a 3-step protocol through definitive endoderm (DE) stage. In parallel, detailed lipidomic analyses as well as gene expression profiling of a set of lipid metabolism-related genes were performed during the entire differentiation process from iPSC to HLCs...
July 21, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28733362/loss-of-cln5-causes-altered-neurogenesis-in-a-childhood-neurodegenerative-disorder
#10
E Savchenko, Y Singh, H Konttinen, K Lejavova, L Mediavilla Santos, A Grubman, V Kärkkäinen, V Keksa-Goldsteine, N Naumenko, P Tavi, A R White, T M Malm, J Koistinaho, K M Kanninen
Neural stem/progenitor cells (NPCs) generate new neurons in the brain throughout the lifetime in an intricate process called neurogenesis. Neurogenic alterations are a common feature of several adult-onset neurodegenerative diseases. The neuronal ceroid lipofuscinoses (NCLs) are the most common group of inherited neurodegenerative diseases that mainly affect children. Pathological features of the NCLs include accumulation of lysosomal storage material, neuroinflammation, and neuronal degeneration, yet the exact cause of this group of diseases remains poorly understood...
July 21, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28714852/the-small-molecule-mimetic-agonist-trimebutine-of-adhesion-molecule-l1-contributes-to-functional-recovery-after-spinal-cord-injury-in-mice
#11
Junping Xu, Chengliang Hu, Qiong Jiang, Hongchao Pan, Huifan Shen, Melitta Schachner
Curing spinal cord injury (SCI) in mammals is a daunting task because of the lack of permissive mechanisms and strong inhibitory responses at and around the lesion. The neural cell adhesion molecule L1CAM (L1) has been shown to favor axonal regrowth and enhance neuronal survival and synaptic plasticity, and thus constitutes a viable target to promote regeneration after SCI. Since delivery of full-length L1 or its extracellular domain could encounter difficulties in translation to therapy in humans, we have identified several small organic compounds that bind to L1 and stimulate neuronal survival, neuronal migration, and neurite outgrowth in an L1-dependent manner...
July 14, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28714851/pdgfr%C3%AE-functions-in-endothelial-derived-cells-to-regulate-neural-crest-cells-and-development-of-the-great-arteries
#12
Haig Aghajanian, Young Kuk Cho, Nicholas W Rizer, Qiaohong Wang, Li Li, Karl Degenhardt, Rajan Jain
Originating as a single vessel emerging from the embryonic heart, the truncus arteriosus must septate and remodel into the aorta and pulmonary artery to support postnatal life. Defective remodeling or septation leads to abnormalities collectively known as conotruncal defects, which are associated with significant mortality and morbidity. Multiple populations of cells must interact to coordinate outflow tract remodeling, and cardiac neural crest has emerged as particularly important during this process. Abnormalities in cardiac neural crest have been implicated in the pathogenesis of multiple conotruncal defects, including persistent truncus arteriosus, double outlet right ventricle, and tetralogy of Fallot...
July 14, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28768736/congenital-diaphragmatic-hernias-from-genes-to-mechanisms-to-therapies
#13
REVIEW
Gabrielle Kardon, Kate G Ackerman, David J McCulley, Yufeng Shen, Julia Wynn, Linshan Shang, Eric Bogenschutz, Xin Sun, Wendy K Chung
Congenital diaphragmatic hernias (CDHs) and structural anomalies of the diaphragm are a common class of congenital birth defects that are associated with significant morbidity and mortality due to associated pulmonary hypoplasia, pulmonary hypertension and heart failure. In ∼30% of CDH patients, genomic analyses have identified a range of genetic defects, including chromosomal anomalies, copy number variants and sequence variants. The affected genes identified in CDH patients include transcription factors, such as GATA4, ZFPM2, NR2F2 and WT1, and signaling pathway components, including members of the retinoic acid pathway...
August 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28768735/therapeutic-strategies-for-spinal-muscular-atrophy-smn-and-beyond
#14
REVIEW
Melissa Bowerman, Catherina G Becker, Rafael J Yáñez-Muñoz, Ke Ning, Matthew J A Wood, Thomas H Gillingwater, Kevin Talbot
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN) due to inactivating mutations in the encoding gene SMN1 A second duplicated gene, SMN2, produces very little but sufficient functional protein for survival. Therapeutic strategies to increase SMN are in clinical trials, and the first SMN2-directed antisense oligonucleotide (ASO) therapy has recently been licensed...
August 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28768734/human-tissue-models-in-cancer-research-looking-beyond-the-mouse
#15
EDITORIAL
Samuel J Jackson, Gareth J Thomas
Mouse models, including patient-derived xenograft mice, are widely used to address questions in cancer research. However, there are documented flaws in these models that can result in the misrepresentation of human tumour biology and limit the suitability of the model for translational research. A coordinated effort to promote the more widespread development and use of 'non-animal human tissue' models could provide a clinically relevant platform for many cancer studies, maximising the opportunities presented by human tissue resources such as biobanks...
August 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28645892/meis1-effects-on-motor-phenotypes-and-the-sensorimotor-system-in-mice
#16
Aaro V Salminen, Lillian Garrett, Barbara Schormair, Jan Rozman, Florian Giesert, Kristina M Niedermeier, Lore Becker, Birgit Rathkolb, Ildikó Rácz, Martin Klingenspor, Thomas Klopstock, Eckhard Wolf, Andreas Zimmer, Valérie Gailus-Durner, Miguel Torres, Helmut Fuchs, Martin Hrabě de Angelis, Wolfgang Wurst, Sabine M Hölter, Juliane Winkelmann
MEIS1 encodes a developmental transcription factor and has been linked to restless legs syndrome (RLS) in genome-wide association studies. RLS is a movement disorder leading to severe sleep reduction and has a substantial impact on the quality of life of patients. In genome-wide association studies, MEIS1 has consistently been the gene with the highest effect size and functional studies suggest a disease-relevant downregulation. Therefore, haploinsufficiency of Meis1 could be the system with the most potential for modeling RLS in animals...
August 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28623239/-ccug-n-rna-toxicity-in-a-drosophila-model-of-myotonic-dystrophy-type-2-dm2-activates-apoptosis
#17
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)...
August 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28615189/bar-coding-neurodegeneration-identifying-subcellular-effects-of-human-neurodegenerative-disease-proteins-using-drosophila-leg-neurons
#18
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. Although different proteins are typically involved in different diseases, 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...
August 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28600349/a-mouse-model-of-hereditary-coproporphyria-identified-in-an-enu-mutagenesis-screen
#19
Ashlee J Conway, Fiona C Brown, Robert O Fullinfaw, Benjamin T Kile, Stephen M Jane, David J Curtis
A genome-wide ethyl-N-nitrosourea (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 blood cell phenotype in heterozygous mice...
August 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28600348/loss-of-the-wnt-receptor-frizzled-7-in-the-mouse-gastric-epithelium-is-deleterious-and-triggers-rapid-repopulation-in-vivo
#20
Dustin J Flanagan, Nick Barker, Cameron Nowell, Hans Clevers, Matthias Ernst, Toby J Phesse, Elizabeth Vincan
The gastric epithelium consists of tubular glandular units, each containing several differentiated cell types, and populations of stem cells, which enable the stomach to secrete the acid, mucus and various digestive enzymes required for its function. 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 of signalling pathways that regulate homeostasis of the diseased organ. Therefore, it is important to understand the biology of how normal conditions are maintained in a tissue to help inform the mechanisms driving disease in that same tissue, and to identify potential points of therapeutic intervention...
August 1, 2017: Disease Models & Mechanisms
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