DOCSLIB.ORG

Enhancing the Astrocytic Clearance of Extracellular Α-Synuclein

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Enhancing the Astrocytic Clearance of Extracellular Α-Synuclein Cellular and Molecular Neurobiology (2019) 39:1017–1028 https://doi.org/10.1007/s10571-019-00696-2 ORIGINAL RESEARCH Enhancing the Astrocytic Clearance of Extracellular α‑Synuclein Aggregates by Ginkgolides Attenuates Neural Cell Injury Jun Hua1,2 · Nuo Yin1 · Shi Xu1 · Qiang Chen1,3 · Tingting Tao1,3 · Ji Zhang4 · Jianhua Ding1 · Yi Fan1,3 · Gang Hu1,5 Received: 9 November 2018 / Accepted: 1 June 2019 / Published online: 5 June 2019 © Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract The accumulation of aggregated forms of the α-Synuclein (α-Syn) is associated with the pathogenesis of Parkinson’s dis- ease (PD), and the efcient clearance of aggregated α-Syn represents a potential approach in PD therapy. Astrocytes are the most numerous glia cells in the brain and play an essential role in supporting brain functions in PD state. In the present study, we demonstrated that cultured primary astrocytes engulfed and degraded extracellular aggregated recombinant human α-Syn. Meanwhile, we observed that the clearance of α-Syn by astrocytes was abolished by proteasome inhibitor MG132 and autophagy inhibitor 3-methyladenine (3MA). We further showed that intracellular α-Syn was reduced after ginkgolide B (GB) and bilobalide (BB) treatment, and the decrease was reversed by MG132 and 3MA. More importantly, GB and BB reduced indirect neurotoxicity to neurons induced by α-Syn-stimulated astrocytic conditioned medium. Together, we frstly fnd that astrocytes can engulf and degrade α-Syn aggregates via the proteasome and autophagy pathways, and further show that GB and BB enhance astrocytic clearance of α-Syn, which gives us an insight into the novel therapy for PD in future. Keywords α-Synuclein · Astrocytes · Autophagy · Ginkgolide B · Bilobalide Abbreviations BCA Bicinchoninic acid α-Syn α-Synuclein CM Conditioned medium ALP Autophagy–lysosome pathways DAPI 4,6-Linked amidine-2-phenylindole BB Bilobalide DLB Dementia with LBs DMSO Dimethyl sulfoxide DTT DL-Dithiothreitol Jun Hua and Nuo Yin have contributed equally to this work. GB Ginkgolide B * Yi Fan GBE Ginkgo biloba extract [email protected] GFAP Glial fbrillary acidic protein * Gang Hu LBs Lewy bodies [email protected] LC3 Microtubule-associated protein 1A/1B-light chain 3 1 Jiangsu Key Laboratory of Neurodegeneration, Department LDH Lactate dehydrogenase of Pharmacology, Nanjing Medical University, 101 Longmian Road, Nanjing 211166, Jiangsu, China LNs Lewy neuritis MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra- 2 Department of Neurology & Psychology, The Fourth Clinical Medical College of Guangzhou University of Chinese zolium Medicine, 1 Fuhua Road, Shenzhen 518033, Guangdong, PBS Phosphate bufered saline China PD Parkinson’s disease 3 Neuroprotective Drug Discovery Key Laboratory of Nanjing SNpc Substantia Nigra pars compacta Medical University, 101 Longmian Road, Nanjing 211166, ThT Thiofavin T Jiangsu, China 3MA 3-Methyladenine 4 Division of Clinical Pharmacy, Department of Pharmacy, UPS Ubiquitin proteasome system The First Afliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China 5 Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing 210023, Jiangsu, China Vol.:(0123456789)1 3 1018 Cellular and Molecular Neurobiology (2019) 39:1017–1028 Introduction overexpression of PLK2 reduced intra-neuronal human α-Syn accumulation, and suppressed dopaminergic neu- Alpha-Synuclein (α-Syn), a 14 kDa protein (140 amino rodegeneration induced by α-Syn overexpression in a rat acids) physiologically found in presynaptic terminals of genetic model of PD (Oueslati et al. 2013). Moreover, neurons, is the major fbrillary protein in Lewy bodies clearance of α-Syn monomers and aggregates occurs via (LBs) and Lewy neuritis (LNs) (Vekrellis et al. 2011). direct proteolysis by matrix metalloprotease 9 (MMP-9) Alpha-Syn has been suggested to play important roles in (Iwata et al. 2003) or binding to molecular chaperones brain lipid metabolism, modulation of synaptic transmis- such as the proteasome (McNaught et al. 2002) and sion, and synaptic vesicle biogenesis (Kim and Lee 2008). autophagy (Oueslati et al. 2013). However, mounting evidence has indicated that α-Syn We have previously shown that aggregated α-Syn induced malfunction, especially the accumulation of misfolded cell apoptosis, and Ginkgo biloba extract (GBE), including α-Syn aggregates and genetic mutations, can also contrib- ginkgolide B (GB) and bilobalide (BB), attenuated aggre- ute to synucleinopathies such as dementia with LBs (DLB) gated α-Syn-induced cell apoptosis (Hua et al. 2017). In the and sporadic and inherited Parkinson’s disease (PD) (Kalia present study, we showed that astrocytes internalized and and Lang 2015; Spillantini et al. 1998). eliminated α-Syn aggregates in vitro, and GB and BB pro- PD is primarily characterized by selective loss of dopa- moted the degradation of intercellular α-Syn aggregates via minergic neurons in the substantia nigra pars compacta the autophagy and proteasome pathways. Moreover, GB and (SNpc) and abrogation of dopaminergic tone along the BB reduced the indirect neurotoxicity of α-Syn to neurons nigrostriatal pathway (Dauer and Przedborski 2003; Obeso in vitro. Herein, we elucidate that the promotion of astro- et al. 2017). However, previous studies have indicated cytic clearance of α-Syn may be a potential approach in PD that the progressive neuronal accumulation of aggregated therapy. α-Syn and the formation of LBs might trigger neuroin- fammation, neurotoxicity, and synaptic dysfunction in PD (Gao et al. 2011; Ma et al. 2014; Volpicelli-Daley et al. Materials and Methods 2011). Notably, the release of α-Syn aggregates from neu- ronal cells was signifcantly increased under PD condition Experimental Animals and Drug Administration (Jang et al. 2010), and extracellular α-Syn aggregates may cause paracrine efects on neighboring cells. Transmission All study protocols were approved by the Institutional Ani- of α-Syn aggregates from neuron-to-neuron (Tyson et al. mal Care and Use Committee of Nanjing Medical University 2017) and neuron-to-glia has been suggested as the under- (IACUC). C57BL/6 mice were provided by Model Animal lying mechanism of neuroinfammation and neurotoxicity Resource Center (MARC, Nanjing, China). All mice were in PD (Choi et al. 2018). Hence, an efcient clearance of maintained on a 12/12 h light/dark cycle with free access to this protein might represent a potential approach in PD food and water. therapy. GB and BB (purity > 99%, supplied by the National Insti- Astrocytes are the most numerous and multifunctional tutes for Food and Drug Control, China) were dissolved in type of glia cells in the central nervous system (CNS). dimethyl sulfoxide (DMSO) as stock solutions for in vitro Astrocytes are crucial to the neuronal microenvironment studies, respectively. due to its abilities to maintain tissue structure, provide nutrition and energy to neurons, and regulate synaptic Cell Culture and Treatment development and neurotransmitter uptake. Previously studies have shown that extracellular α-Syn acted on neu- Primary astrocytes were prepared from brains of 1- to ronal Toll-like receptor 2 (TLR2) might result in neuro- 2-day-old C57BL/6 mice, as previously described (Zeng degeneration by inhibition of autophagy via AKT/mTOR et al. 2007). Briefy, neonates (P1–2) were killed by rapid signaling (Kim et al. 2013), while extracellular α-Syn decapitation. The midbrain was removed, and then the tis- activated microglia via NF-κB and p38 MAPK pathway, sue was dissociated with 0.25% tryptase (VWR Life Sci- thereby resulted in neuroinfammatory factors produc- ence, USA) at 37 °C and terminated by Dulbecco’s Modifed tion (Kim et al. 2015). While extracellular α-Syn aggre- Eagle’s Medium (DMEM, Gibco Lab., USA) supplemented gates can be taken up by neurons (Lee et al. 2008a, b) and with 10% Fetal Bovine Serum (FBS, Gibco Lab., USA), glial cells (Lee et al. 2008a, b) by endocytosis, it is not and 100 mg/mL streptomycin (Sigma-Aldrich Biotechnol- clear whether astrocytes are responsible for α-Syn clear- ogy, USA) and 100 U/mL penicillin (Gibco Lab., USA). ance in PD. A recent study reported that Polo-like kinase After centrifugation at 1500 rpm for 5 min, the cell pellets 2 (PLK2) enhanced α-Syn autophagic degradation, and were re-suspended and plated on a poly-lysine-treated fask (Sigma, St Louis, MO). The cultures were maintained at 1 3 Cellular and Molecular Neurobiology (2019) 39:1017–1028 1019 37 °C in a humidifed 5% CO2–95% air atmosphere. Culture and 5 μL α-Syn sample were added to the 96-well plate to media were changed 24 h later to complete medium and sub- a fnal volume of 200 μL. Phosphate bufered saline (PBS) sequently twice a week. The purity of astrocyte was > 95% was as a blank control. The reaction was carried out at room as determined with GFAP immunocytochemistry. Before temperature for 1 min, and the absorbance value was read experimental treatments, astrocytic cultures were passaged by a full-wavelength microplate reader. The excitation light once. is 446 nm and the absorption light is 482 nm. ThT binding Human neuroblastoma SH-SY5Y cells were purchased (unit a.u.) = Absorbance of Sample − Absorbance of PBS from American Type Culture Collection (ATCC, USA). blank control. Cells were cultured in DMEM (Gibco Lab., USA) contain- ing 10% FBS (Gibco Lab., USA), 100 mg/mL streptomycin (Sigma-Aldrich Biotechnology, USA), and 100 U/mL peni- FITC‑labeled α‑Syn Aggregates cillin (Gibco Lab., USA). The cultures were maintained at 37 °C in a humidifed atmosphere of 5% CO 2 and 95% air. The α-Syn aggregates were placed in 4-mL ultrafltration Before the experiments, cells were inoculated into 6-well tubes (30 kDa, Millipore, UFC803008) and centrifuged at plate or 96-well plate, and cultured in DMEM containing 7500 g for 20 min, following replaced PBS with a freshly 10% FBS for 24 h. Then the medium was replaced with prepared cross-linked reaction solution (7.56 g NaHCO3, serum-free medium with α-Syn (1 μM) or GB (10 μM)/ 1.06 g Na2CO3, 7.36 g NaCl, pH 9.0, plus ddH2O fxed BB (10 μM) or MG132 (20 μM)/3MA (5 mM) in diferent volume to 1 L).
Load more

Recommended publications
  • The Role and Mechanisms of Action of Micrornas in Cancer Drug Resistance Wengong Si1,2,3, Jiaying Shen4, Huilin Zheng1,5 and Weimin Fan1,6*
    Si et al. Clinical Epigenetics (2019) 11:25 https://doi.org/10.1186/s13148-018-0587-8 REVIEW Open Access The role and mechanisms of action of microRNAs in cancer drug resistance Wengong Si1,2,3, Jiaying Shen4, Huilin Zheng1,5 and Weimin Fan1,6* Abstract MicroRNAs (miRNAs) are small non-coding RNAs with a length of about 19–25 nt, which can regulate various target genes and are thus involved in the regulation of a variety of biological and pathological processes, including the formation and development of cancer. Drug resistance in cancer chemotherapy is one of the main obstacles to curing this malignant disease. Statistical data indicate that over 90% of the mortality of patients with cancer is related to drug resistance. Drug resistance of cancer chemotherapy can be caused by many mechanisms, such as decreased antitumor drug uptake, modified drug targets, altered cell cycle checkpoints, or increased DNA damage repair, among others. In recent years, many studies have shown that miRNAs are involved in the drug resistance of tumor cells by targeting drug-resistance-related genes or influencing genes related to cell proliferation, cell cycle, and apoptosis. A single miRNA often targets a number of genes, and its regulatory effect is tissue-specific. In this review, we emphasize the miRNAs that are involved in the regulation of drug resistance among different cancers and probe the mechanisms of the deregulated expression of miRNAs. The molecular targets of miRNAs and their underlying signaling pathways are also explored comprehensively. A holistic understanding of the functions of miRNAs in drug resistance will help us develop better strategies to regulate them efficiently and will finally pave the way toward better translation of miRNAs into clinics, developing them into a promising approach in cancer therapy.
    [Show full text]
  • Principles and Applications of Rabbit Models for Atherosclerosis Research
    J Atheroscler Thromb, 2018; 25: 213-220. http://doi.org/10.5551/jat.RV17018 Review Principles and Applications of Rabbit Models for Atherosclerosis Research Jianglin Fan1, Yajie Chen1, Haizhao Yan1, Manabu Niimi1, Yanli Wang2 and Jingyan Liang3 1Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan 2Department of Pathology, Xi’an Medical University, Xi’an, China 3Research Center for Vascular Biology, Yangzhou University School of Medicine, Yangzhou, China Rabbits are one of the most used experimental animals for biomedical research, particularly as a bio- reactor for the production of antibodies. However, many unique features of the rabbit have also made it as an excellent species for examining a number of aspects of human diseases such as atherosclerosis. Rabbits are phylogenetically closer to humans than rodents, in addition to their relatively proper size, tame disposition, and ease of use and maintenance in the laboratory facility. Due to their short life spans, short gestation periods, high numbers of progeny, low cost (compared with other large ani- mals) and availability of genomics and proteomics, rabbits usually serve to bridge the gap between smaller rodents (mice and rats) and larger animals, such as dogs, pigs and monkeys, and play an important role in many translational research activities such as pre-clinical testing of drugs and diag- nostic methods for patients. The principle of using rabbits rather than other animals as an experi- mental model is very simple: rabbits should be used for research, such as translational research, that is difficult to accomplish with other species. Recently, rabbit genome sequencing and transcriptomic profiling of atherosclerosis have been successfully completed, which has paved a new way for researchers to use this model in the future.
    [Show full text]
  • WO 2017/147196 Al 31 August 2017 (31.08.2017) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/147196 Al 31 August 2017 (31.08.2017) P O P C T (51) International Patent Classification: Kellie, E. [US/US]; 70 Lanark Road, Maiden, MA 02148 C12Q 1/68 (2006.01) (US). COLE, Michael, B. [US/US]; 233 1 Eunice Street, Berkeley, CA 94708 (US). YOSEF, Nir [IL/US]; 1520 (21) International Application Number: Laurel Ave., Richmond, CA 94805 (US). GAYO, En¬ PCT/US20 17/0 18963 rique, Martin [ES/US]; 115 Peterborough Street, Boston, (22) International Filing Date: MA 022 15 (US). OUYANG, Zhengyu [CN/US]; 15 Vas- 22 February 2017 (22.02.2017) sar Street, Medford, MA 02155 (US). YU, Xu [CN/US]; 6 Whittier Place, Apt. 16j, Boston, MA 02 114 (US). (25) Filing Language: English (74) Agents: KOWALSKI, Thomas, J. et al; Vedder Price English (26) Publication Language: P.C., 1633 Broadway, New York, NY 1001 9 (US). (30) Priority Data: (81) Designated States (unless otherwise indicated, for every 62/298,349 22 February 2016 (22.02.2016) US kind of national protection available): AE, AG, AL, AM, (71) Applicants: MASSACHUSETTS INSTITUTE OF AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, TECHNOLOGY [US/US]; 77 Massachusetts Ave., Cam BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, bridge, MA 02139 (US). THE REGENTS OF THE UNI¬ DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, VERSITY OF CALIFORNIA [US/US]; 1111 Franklin HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, Street, 12th Floor, Oakland, CA 94607 (US).
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Test Catalogue August 2019
    Test Catalogue August 2019 www.centogene.com/catalogue Table of Contents CENTOGENE CLINICAL DIAGNOSTIC PRODUCTS AND SERVICES › Whole Exome Testing 4 › Whole Genome Testing 5 › Genome wide CNV Analysis 5 › Somatic Mutation Analyses 5 › Biomarker Testing, Biochemical Testing 6 › Prenatal Testing 7 › Additional Services 7 › Metabolic Diseases 9 - 21 › Neurological Diseases 23 - 47 › Ophthalmological Diseases 49 - 55 › Ear, Nose and Throat Diseases 57 - 61 › Bone, Skin and Immune Diseases 63 - 73 › Cardiological Diseases 75 - 79 › Vascular Diseases 81 - 82 › Liver, Kidney and Endocrinological Diseases 83 - 89 › Reproductive Genetics 91 › Haematological Diseases 93 - 96 › Malformation and/or Retardation Syndromes 97 - 107 › Oncogenetics 109 - 113 ® › CentoXome - Sequencing targeting exonic regions of ~20.000 genes Test Test name Description code CentoXome® Solo Medical interpretation/report of WES findings for index 50029 CentoXome® Solo - Variants Raw data; fastQ, BAM, Vcf files along with variant annotated file in xls format for index 50028 CentoXome® Solo - with CNV Medical interpretation/report of WES including CNV findings for index 50103 Medical interpretation/report of WES in index, package including genome wide analyses of structural/ CentoXome® Solo - with sWGS 50104 large CNVs through sWGS Medical interpretation/report of WES in index, package including genome wide analyses of structural/ CentoXome® Solo - with aCGH 750k 50122 large CNVs through 750k microarray Medical interpretation/report of WES in index, package including genome
    [Show full text]
  • Metabotropic Glutamate Receptor 5 Inhibits Α-Synuclein-Induced
    Zhang et al. Journal of Neuroinflammation (2021) 18:23 https://doi.org/10.1186/s12974-021-02079-1 RESEARCH Open Access Metabotropic glutamate receptor 5 inhibits α-synuclein-induced microglia inflammation to protect from neurotoxicity in Parkinson’s disease Ya-Nan Zhang1, Jing-Kai Fan1,LiGu1, Hui-Min Yang1, Shu-Qin Zhan2,3 and Hong Zhang1* Abstract Background: Microglia activation induced by α-synuclein (α-syn) is one of the most important factors in Parkinson’s disease (PD) pathogenesis. However, the molecular mechanisms by which α-syn exerts neuroinflammation and neurotoxicity remain largely elusive. Targeting metabotropic glutamate receptor 5 (mGluR5) has been an attractive strategy to mediate microglia activation for neuroprotection, which might be an essential regulator to modulate α- syn-induced neuroinflammation for the treatment of PD. Here, we showed that mGluR5 inhibited α-syn-induced microglia inflammation to protect from neurotoxicity in vitro and in vivo. Methods: Co-immunoprecipitation assays were utilized to detect the interaction between mGluR5 and α-syn in microglia. Griess, ELISA, real-time PCR, western blotting, and immunofluorescence assays were used to detect the regulation of α-syn-induced inflammatory signaling, cytokine secretion, and lysosome-dependent degradation. Results: α-syn selectively interacted with mGluR5 but not mGluR3, and α-syn N terminal deletion region was essential for binding to mGluR5 in co-transfected HEK293T cells. The interaction between these two proteins was further detected in BV2 microglia, which was inhibited by the mGluR5 specific agonist CHPG without effect by its selective antagonist MTEP. Moreover, in both BV2 cells and primary microglia, activation of mGluR5 by CHPG partially inhibited α-syn-induced inflammatory signaling and cytokine secretion and also inhibited the microglia activation to protect from neurotoxicity.
    [Show full text]
  • Genome-Wide Analysis of DNA Methylation in Human Peripheral Leukocytes Identifies Potential Biomarkers of Nonalcoholic Fatty Liver Disease
    INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 42: 443-452, 2018 Genome-wide analysis of DNA methylation in human peripheral leukocytes identifies potential biomarkers of nonalcoholic fatty liver disease RUI-NAN ZHANG1, QIN PAN1, RUI-DAN ZHENG2, YU-QIANG MI3, FENG SHEN1, DA ZHOU1, GUANG-YU CHEN1, CHAN-YAN ZHU1 and JIAN-GAO FAN1 1Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092; 2Diagnosis and Treatment Center for Liver Diseases, Zhengxing Hospital, Zhangzhou, Fujian 363000; 3Department of Infective Diseases, Tianjin Infectious Disease Hospital, Tianjin 300192, P.R. China Received November 24, 2016; Accepted February 12, 2018 DOI: 10.3892/ijmm.2018.3583 Abstract. The aim of the present study was to uncover the NAFLD patients from normal controls. The leukocytic role of leukocytic DNA methylation in the evaluation of hypomethylated ACSL4 (cg15536552) was suggested to be a nonalcoholic fatty liver disease (NAFLD). Patients with biomarker for the pathological characteristics of NAFLD. biopsy-proven NAFLD (n=35) and normal controls (n=30) were recruited from Chinese Han population. Their DNA Introduction methylation in peripheral leukocytes was subjected to genome-wide profiling. The association between differential Nonalcoholic fatty liver disease (NAFLD) is a metabolic-related methylation of CpG sites and NAFLD was further investigated liver disease associated with obesity, insulin resistance (IR), on the basis of histopathological classification, bioinformatics, type 2 diabetes mellitus (T2DM), and other components of the and pyrosequencing. A panel of 863 differentially methylated metabolic syndrome (MetS). Proportionally, it is now the most CpG sites dominated by global hypomethylation, character- common chronic liver disease worldwide (1).
    [Show full text]
  • Myeloid Innate Immunity Mouse Vapril2018
    Official Symbol Accession Alias / Previous Symbol Official Full Name 2810417H13Rik NM_026515.2 p15(PAF), Pclaf RIKEN cDNA 2810417H13 gene 2900026A02Rik NM_172884.3 Gm449, LOC231620 RIKEN cDNA 2900026A02 gene Abcc8 NM_011510.3 SUR1, Sur, D930031B21Rik ATP-binding cassette, sub-family C (CFTR/MRP), member 8 Acad10 NM_028037.4 2410021P16Rik acyl-Coenzyme A dehydrogenase family, member 10 Acly NM_134037.2 A730098H14Rik ATP citrate lyase Acod1 NM_008392.1 Irg1 aconitate decarboxylase 1 Acot11 NM_025590.4 Thea, 2010309H15Rik, 1110020M10Rik,acyl-CoA Them1, thioesterase BFIT1 11 Acot3 NM_134246.3 PTE-Ia, Pte2a acyl-CoA thioesterase 3 Acox1 NM_015729.2 Acyl-CoA oxidase, AOX, D130055E20Rikacyl-Coenzyme A oxidase 1, palmitoyl Adam19 NM_009616.4 Mltnb a disintegrin and metallopeptidase domain 19 (meltrin beta) Adam8 NM_007403.2 CD156a, MS2, E430039A18Rik, CD156a disintegrin and metallopeptidase domain 8 Adamts1 NM_009621.4 ADAM-TS1, ADAMTS-1, METH-1, METH1a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 1 Adamts12 NM_175501.2 a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 12 Adamts14 NM_001081127.1 Adamts-14, TS14 a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 14 Adamts17 NM_001033877.4 AU023434 a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 17 Adamts2 NM_001277305.1 hPCPNI, ADAM-TS2, a disintegrin and ametalloproteinase disintegrin-like and with metallopeptidase thrombospondin
    [Show full text]
  • Genetics: FAN1 Mutations Result in Defective DNA Damage Repair and Karyomegalic Interstitial Nephritis
    RESEARCH HIGHLIGHTS Nature Reviews Nephrology 8, 491 (2012); published online 24 July 2012; doi:10.1038/nrneph.2012.146 GENETICS FAN1 mutations result in defective DNA damage repair and karyomegalic interstitial nephritis utations in FAN1 lead to a independently of the Fanconi anaemia defective DNA damage response pathway. In support of this theory, the M(DDR) and karyomegalic researchers found that depletion of interstitial nephritis (KIN), according to FANCD2 in FAN1-mutant cells resulted in new research. “Our findings implicate a worsening of the mitomycin C sensitivity susceptibility to environmental genotoxins defect, suggesting additive pathways. and inadequate DNA repair as novel Most DDR pathways and NPHP-like mechanisms contributing to renal fibrosis ciliopathies are conserved in zebrafish; and [chronic kidney disease]”, state therefore, the researchers performed the researchers. morpholino oligonucleotide knockdown To identify causative genes for of fan1 in zebrafish embryos. Knockdown nephronophthisis (NPHP)-like ciliopathies, of fan1 resulted in NPHP-like and DDR Weibin Zhou, Edgar Otto et al. examined phenotypes, characterized by a shortened two affected siblings of New Zealand Maori body axis, microcephaly, microphthalmia descent. Renal histology demonstrated the and massive apoptotic cell death. Zhou presence of enlarged nuclei (karyomegaly), * et al. found increased levels of γH2AX, leading to a diagnosis of KIN—a rare indicative of activated DDR signalling. NPHP-like fibrotic kidney disease. The Suppressing apoptosis by knocking researchers performed homozygosity * down p53 function revealed phenotypes mapping and exome sequencing, revealing characteristic of NPHP-like ciliopathies, a homozygous nonsense mutation in including pronephric renal cysts. “Loss of FAN1, which encodes Fanconi anemia- fan1 function results in ciliopathy-related Zebrafish embryos with knockdown of p53 alone at associated nuclease 1.
    [Show full text]
  • Characterizing Genomic Duplication in Autism Spectrum Disorder by Edward James Higginbotham a Thesis Submitted in Conformity
    Characterizing Genomic Duplication in Autism Spectrum Disorder by Edward James Higginbotham A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Molecular Genetics University of Toronto © Copyright by Edward James Higginbotham 2020 i Abstract Characterizing Genomic Duplication in Autism Spectrum Disorder Edward James Higginbotham Master of Science Graduate Department of Molecular Genetics University of Toronto 2020 Duplication, the gain of additional copies of genomic material relative to its ancestral diploid state is yet to achieve full appreciation for its role in human traits and disease. Challenges include accurately genotyping, annotating, and characterizing the properties of duplications, and resolving duplication mechanisms. Whole genome sequencing, in principle, should enable accurate detection of duplications in a single experiment. This thesis makes use of the technology to catalogue disease relevant duplications in the genomes of 2,739 individuals with Autism Spectrum Disorder (ASD) who enrolled in the Autism Speaks MSSNG Project. Fine-mapping the breakpoint junctions of 259 ASD-relevant duplications identified 34 (13.1%) variants with complex genomic structures as well as tandem (193/259, 74.5%) and NAHR- mediated (6/259, 2.3%) duplications. As whole genome sequencing-based studies expand in scale and reach, a continued focus on generating high-quality, standardized duplication data will be prerequisite to addressing their associated biological mechanisms. ii Acknowledgements I thank Dr. Stephen Scherer for his leadership par excellence, his generosity, and for giving me a chance. I am grateful for his investment and the opportunities afforded me, from which I have learned and benefited. I would next thank Drs.
    [Show full text]
  • The Novel ZIP4 Regulation and Its Role in Ovarian Cancer
    www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 52), pp: 90090-90107 Research Paper The novel ZIP4 regulation and its role in ovarian cancer Qipeng Fan1, Qingchun Cai1, Pengfei Li1,2, Wenyan Wang1,3, Jing Wang1,4, Emily Gerry5, Tian-Li Wang5, Ie-Ming Shih5, Kenneth P. Nephew6 and Yan Xu1 1Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN 46202, USA 2Pharmaceutical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, P.R. China 3Department of Obstetrics and Gynecology, The Second Hospital of Anhui Medical University, Hefei City, 230601, P.R. China 4MASDINO (Beijing) Medical Research Co. Ltd., Beijing, 100123, P.R. China 5Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA 6Medical Sciences, Indiana University School of Medicine, Jordan Hall 302, Bloomington, IN 47405, USA Correspondence to: Yan Xu, email: [email protected] Keywords: ZIP4, LPA, ovarian cancer, cancer stem cells (CSC) Received: June 07, 2017 Accepted: August 26, 2017 Published: September 30, 2017 Copyright: Fan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Our RNAseq analyses revealed that ZIP4 is a top gene up-regulated in more aggressive ovarian cancer cells. ZIP4’s role in cancer stem cells has not been reported in any type of cancer. In addition, the role and regulation of ZIP4, a zinc transporter, have been studied in the context of extracellular zinc transporting.
    [Show full text]
  • Karyomegalic Interstitial Nephritis and DNA Damage-Induced Polyploidy in Fan1 Nuclease-Defective Knock-In Mice
    Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press RESEARCH COMMUNICATION Fancd2 ubiquitylation (K561) causes defective ICL repair Karyomegalic interstitial (Garcia-Higuera et al. 2001; Knipscheer et al. 2009; Deans nephritis and DNA damage- and West 2011). Fan1 is a 5′ flap endonuclease recruited to sites where induced polyploidy in Fan1 replisomes stall—for example, at ICLs—in a manner that requires Fancd2 ubiquitylation (Kratz et al. 2010; Liu et al. nuclease-defective knock-in 2010; MacKay et al. 2010; Smogorzewska et al. 2010). The mice nuclease activities of Fan1 are mediated by a C-terminal “ ” 1 1 VRR_nuc domain (Iyer et al. 2006), which is conserved Christophe Lachaud, Meghan Slean, in all orthologs as far back as yeasts. Fan1 also has a SAP- Francesco Marchesi,2 Claire Lock,3 Edward Odell,3 type DNA-binding domain and a UBZ4-type ubiquitin- Dennis Castor,1,4 Rachel Toth,1 binding domain, which interacts with ubiquityl-Fancd2, and John Rouse1 thereby recruiting Fan1 to sites of replisome stalling. Fan1 is required for efficient ICL repair, but, surprisingly, 1MRC Protein Phosphorylation and Ubiquitylation Unit, College this does not require interaction with ubiquityl-Fancd2 of Life Sciences, Sir James Black Centre, University of Dundee, (Lachaud et al. 2016). Similarly, genetic analyses in worms Dundee DD1 5EH, United Kingdom 2School of Veterinary and human cells showed that Fan1 and Fancd2 mutations Medicine, College of Medical, Veterinary, and Life Sciences, are not epistatic with respect to hypersensitivity to ICL- University of Glasgow, Glasgow G61 1QH, United Kingdom inducing drugs, suggesting that the two genes are not 3Department of Head and Neck Pathology, Guy’s Hospital, equivalent in function when it comes to ICL repair (Yosh- London SE1 9RT, United Kingdom ikiyo et al.
    [Show full text]