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2014, August 13-17 Journal of Inborn Errors of Metabolism &Screening 1–103 Abstracts of Free Communications ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav Accepted for Presentation at the DOI: 10.1177/2326409814538909 13th International Symposium on iem.sagepub.com Mucopolysaccharidoses and Related Diseases, Sauipe, Bahia, Brazil, August 13-17, 2014 1. Animal Models parameters such as the sperm production and the integrity of testicular interstitial compartment, possibly as a conse- quence of the glycosaminoglycan storage progression. 1017 - Reproductive Characteristics of Male On the other hand, sperm once produced do not appear Mucopolysaccharidosis Type I Murine Model abnormal. Financial Support: AFIP, Coordenac¸a˜odeAper- Assed in 2 Different Ages feic¸oamento de Pessoal de Nı´vel Superior (CAPES), Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo´gico(CNPq), Cinthia Nascimento1, Odair Aguiar1, and Vaˆnia and Fundac¸a˜o de Amparo a Pesquisa do Estado de Sa˜oPaulo (FAPESP). D’Almeida1 1Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil 1045 - Evidence of Caspase-Independent Cell Introduction: Mucopolysaccharidosis type I (MPS) is charac- Death in Murine Mucopolysaccharidosis Type terized by the deficiency of a-L-iduronidase (IDUA) and contin- uous deposition of heparan sulfate and dermatan sulfate in many I Macrophages tissues and organs. Due to the susceptibility of reproductive sys- 1 1 tem to environmental and genetic factors, we considered rele- Karina Cunha e Rocha , Gustavo Monteiro Viana , Edgar 1 1 vant the biological characterization of this system in the Julian Paredes-Gamero , Ana Maria Martins , and Vaˆnia murine model of MPS-I. Objective: To characterize some of the D’Almeida1 male reproductive parameters of MPS-I mice in 2 phases of life. 1Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil Methods: C57BL/6J male mice were distributed in 4 groups according to age (3- or 6-month-old) or genotype (IDUAþ/þ Introduction: Mucopolysaccharidosis type I (MPS-I) is an or IDUAÀ/À). Biometry, sperm production, sperm morphology, autosomal recessive disease caused by the deficiency of plasma testosterone, testicular histology, and histomorphometry a,-L-iduronidase (IDUA), responsible for degradation of were performed. Results: Relative weights of seminal vesicle glycosaminoglycans (GAGs). Besides intralysosomal GAG were lower in 3- and 6-month-old IDUAÀ/À mice than that in accumulation, secondary cellular pathways might be involved the same age controls (P ¼ .016 and P ¼ .001, respectively), in the disease pathophysiology, like lysosomal membrane per- regardless of normal plasma testosterone concentration. Sperm meabilization, autophagy, and cell death. Objectives and morphology was not altered among normal and knockout mice; Methods: To evaluate parameters of cellular homeostasis however, sperm production was lower in 6-month-old IDUAÀ/À such as lysosomal pH (by acridine orange assay), release of mice as previously demonstrated by our group (P ¼ .007), lysosomal cathepsin D (using confocal microscopy), caspase which indicates that the absence of IDUA alters sperm produc- activity (by fluorescent substrate cleavage assay), and relative tion in a quantitative but not necessarily in a qualitative way. expression of apoptotic proteins (Western blotting analysis) in Signs of testicular degeneration were present but not predomi- 3-month-old murine MPS-I macrophages. Results: We found nant in knockout mice; however, interstitial compartment was a significant decrease in lysosomal pH and an increase in more intense stained with toluidine blue, in 6-month-old cathepsin D release to cytoplasm (lysosomal membrane per- IDUAÀ/À mice (P < .0001), suggesting storage of extracellu- meabilization), but no alteration in apoptotic markers in the lar matrix components. Besides that, the percentage of inter- IDUA À/À group compared to the control group. However, stitial was higher in IDUAÀ/À mice than in the controls of when stimulated with Staurosporine (an apoptotic inducer), both age-groups (P ¼ .0002 and P ¼ .048, respectively). cells from the IDUA À/À group showed a higher apoptotic Conclusion: Our results demonstrate that the disruption of rate. Conclusion: Together, these results indicate a possible IDUA in male mice interferes in some of their reproductive mechanism of caspase-independent cell death present in 2 Journal of Inborn Errors of Metabolism & Screening macrophages from MPS-I mice and provide new insights for 1072 - Iduronate-2-Sulfatase Deficiency Leads understanding cellular pathology in this disease. to Early Dysregulation of Bone Development in a Zebrafish Model of Mucopolysaccharido- sis Type II 1070 - Mouse Model of Mucopolysaccharidosis Type IIIC: Distribution and Characterization Stefania Bellesso1, Marika Salvalaio1, Roberto of the Storage Process in Brain and Costa2,IlariaZancan2, Rosella Tomanin1, and Enrico Peripheral Tissues. A Histopathological Moro2 and Electron Microscopical Study 1Department of Women’s and Children’s Health, University of 1 2 2 Padova, Padova, Italy Helena Hu˚lkova´ , Carla Martins , Larbi Dridi , Martin 2 1 2 Department of Molecular Medicine, University of Padova, Padova, Hrˇebı´cˇek , and Alexey Pshezhetsky Italy 1Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Lysosomes are usually considered as end organelles with Charles University in Prague, Prague, Czech Republic the main role of degrading damaged molecules and waste 2CHU Ste-Justine, University of Montreal, Montreal, Canada substrates. However, it has become clear that they also Objectives: To characterize lysosomal storage pattern in brain functionally interact with other organelles, thus taking part and peripheral organs of mice deficient for heparan sulfate in complex cellular regulatory systems. Mutations causing acetyl-CoA:a-glucosaminide N-acetyltransferase (Hgsnat). dysfunction of lysosomal enzymes involved in catabolism This analysis is a part of the complex characterization of the of glycosaminoglycans (GAGs) are responsible for differ- mouse model for mucopolysaccharidosis type IIIC (Pshez- ent types of mucopolysaccharidosis (MPS). These meta- hetsky et al). Methods: Brain, liver, spleen, heart, lungs, kid- bolic disorders are generally considered caused by ney, and skin of mice homozygous for Hgsnat-Geo allele lysosomal accumulation of partially or totally undegraded (Hgsnat-Geo mice) and of their control counterparts were GAGs, leading to organelle impairment and cytotoxicity. examined by histology, histochemistry, immunohistochemis- However, the idea that other early cellular and develop- try, and electron microscopy. Results: The main organs mental defects may contribute to patients’clinical pheno- affected at the optical and the ultrastructural levels were brain types is clearly emerging. Among the different MPS, and liver. Lysosomal storage of material with characteristics of mucopolysaccharidosis type II (MPS-II or Hunter syn- glycosaminoglycans (GAGs) was early detectable in hepato- drome; Online Mendelian Inheritance in Man þ309900), cytes and in splenic sinus endothelium, and later and to a lesser caused by the deficit activity of the lysosomal enzyme extent in liver Kupffer cells, in bronchial respiratory epithe- iduronate 2-sulfatase (IDS), is a complex rare disorder, lium, renal glomeruli, renal tubular epithelium, fibroblasts, in which skeletal abnormalities represent one of the major vascular endothelial cells, and pericytes. Microglia containing disabling aspects. Enzyme replacement therapy is the cur- storage material of GAG type was early detectable in brains of rently available therapeutic option with, however, a limited Hgsnat-Geo mice, preceding structural changes in neurons. efficacy. To better elucidate early alterations in bone Morphological findings in neurons were dominated by progres- development occurring in MPS-II, we took advantage of sing lysosomal storage of autofluorescent ceroid-like material the zebrafish animal model, given its easy genetic manip- and by ultrastructural mitochondrial abnormalities. At the most ulation and evolutionary conservation of mechanisms and advanced stages of the disease, storage compartment con- signaling pathways regulating bone formation. In particu- tained closely packed fibrillary structures often resembling lar, we generated a zebrafish model for MPS-II, using a storage material of a rectilinear and/or fingerprint type in morpholino-based knockdown technology. The morphant neuronal ceroid lipofuscinoses. Pathological changes in neu- fish displays some typical clinical manifestations of rons were accompanied by increase in glial fibrilar acidic patients with Hunter syndrome, such as hepatomegaly, protein staining, pointing to neuronal loss. Conclusion: liver GAGs accumulation, and defects in chondrogenesis Hgsnat-Geo mice developed a widespread lysosomal storage and osteogenesis. Using different approaches, including consistent with accumulation of undegraded GAG in the in situ hybridization and transgenesis, we demonstrate that epithelial and mesenchymal cells, similar to other mouse IDS knock down affects the expression of key fibroblast models of Sanfilippo, but with later onset and lesser intensity. growth factor (FGF) signaling markers at early stages, The GAG storage in brain microglia preceded neuronal changes before a clear lysosomal impairment is detectable. More- that were characterized by lysosomal and mitochondrial altera- over, our results show an altered expression of bone- tion followed
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