Database : MEDLINE
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PMID:27923633
Author:Trilck M; Peter F; Zheng C; Frank M; Dobrenis K; Mascher H; Rolfs A; Frech MJ
Address:Albrecht-Kossel-Institute for Neuroregeneration (AKos), University Medicine Rostock, Gehlsheimer Straße 20, 18147 Rostock, Germany; Institute of Neurogenetics, University of Luebeck, Maria-Goeppert-Str. 1, 23562 Luebeck, Germany. Electronic address: michaela.trilck@neuro.uni-luebeck.de.
Title:Diversity of glycosphingolipid GM2 and cholesterol accumulation in NPC1 patient-specific iPSC-derived neurons.
Source:Brain Res; 1657:52-61, 2017 Feb 15.
ISSN:1872-6240
Country of publication:Netherlands
Language:eng
Abstract:Niemann-Pick disease Type C1 (NPC1) is a rare progressive neurodegenerative disorder caused by mutations in the NPC1 gene. On the cellular level NPC1 mutations lead to an accumulation of cholesterol and gangliosides. As a thorough analysis of the severely affected neuronal cells is unfeasible in NPC1 patients, we recently described the cellular phenotype of neuronal cells derived from NPC1 patient iPSCs carrying the compound heterozygous mutation c.1836A>C/c.1628delC. Here we expanded the analysis to cell lines carrying the prevalent mutation c.3182T>C and the novel mutation c.1180T>C, as well as to the determination of GM2 and GM3 gangliosides in NPC1 patient-specific iPSC-derived neurons and glia cells. Immunocytochemical detection of GM2 revealed punctated staining pattern predominantly localized in neurons. Detection of cholesterol by filipin staining showed a comparable staining pattern, colocalized with GM2, indicating a deposit of GM2 and cholesterol in the same cellular compartments. Accumulations were not only restricted to cell bodies, but were also found in the neuronal extensions. A quantification of the GM2 amount by HPLC-MS/MS confirmed significantly higher amounts in neurons carrying a mutation. Additionally, these cells displayed a lowered activity of the catabolic enzyme Hex A, but not B4GALNT1. Molecular docking simulations indicated binding of cholesterol to Hex A, suggesting cholesterol influences the GM2 degradation pathway and, subsequently, leading to the accumulation of GM2. Taken together, this is the first study showing an accumulation of GM2 in neuronal derivatives of patient-specific iPSCs and thus proving further disease-specific hallmarks in this human in vitro model of NPC1.
Publication type:JOURNAL ARTICLE
Name of substance:0 (Carrier Proteins); 0 (G(M3) Ganglioside); 0 (Membrane Glycoproteins); 0 (NPC1 protein, human); 19600-01-2 (G(M2) Ganglioside); 97C5T2UQ7J (Cholesterol); EC 3.2.1.52 (Hexosaminidase A)


  2 / 380 MEDLINE  
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PMID:27682588
Author:Dersh D; Iwamoto Y; Argon Y
Address:Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104.
Title:Tay-Sachs disease mutations in HEXA target the α chain of hexosaminidase A to endoplasmic reticulum-associated degradation.
Source:Mol Biol Cell; 27(24):3813-3827, 2016 Dec 01.
ISSN:1939-4586
Country of publication:United States
Language:eng
Abstract:Loss of function of the enzyme ß-hexosaminidase A (HexA) causes the lysosomal storage disorder Tay-Sachs disease (TSD). It has been proposed that mutations in the α chain of HexA can impair folding, enzyme assembly, and/or trafficking, yet there is surprisingly little known about the mechanisms of these potential routes of pathogenesis. We therefore investigated the biosynthesis and trafficking of TSD-associated HexA α mutants, seeking to identify relevant cellular quality control mechanisms. The α mutants E482K and G269S are defective in enzymatic activity, unprocessed by lysosomal proteases, and exhibit altered folding pathways compared with wild-type α. E482K is more severely misfolded than G269S, as observed by its aggregation and inability to associate with the HexA ß chain. Importantly, both mutants are retrotranslocated from the endoplasmic reticulum (ER) to the cytosol and are degraded by the proteasome, indicating that they are cleared via ER-associated degradation (ERAD). Leveraging these discoveries, we observed that manipulating the cellular folding environment or ERAD pathways can alter the kinetics of mutant α degradation. Additionally, growth of patient fibroblasts at a permissive temperature or with chemical chaperones increases cellular Hex activity by improving mutant α folding. Therefore modulation of the ER quality control systems may be a potential therapeutic route for improving some forms of TSD.
Publication type:JOURNAL ARTICLE
Name of substance:0 (Molecular Chaperones); EC 3.2.1.52 (Hexosaminidase A); EC 3.2.1.52 (beta-N-Acetylhexosaminidases)


  3 / 380 MEDLINE  
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PMID:25976368
Author:Sims-Robinson C; Bakeman A; Rosko A; Glasser R; Feldman EL
Address:Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA. robinsoc@musc.edu.
Title:The Role of Oxidized Cholesterol in Diabetes-Induced Lysosomal Dysfunction in the Brain.
Source:Mol Neurobiol; 53(4):2287-96, 2016 May.
ISSN:1559-1182
Country of publication:United States
Language:eng
Abstract:Abnormalities in lysosomal function have been reported in diabetes, aging, and age-related degenerative diseases. These lysosomal abnormalities are an early manifestation of neurodegenerative diseases and often precede the onset of clinical symptoms such as learning and memory deficits; however, the mechanism underlying lysosomal dysfunction is not known. In the current study, we investigated the mechanism underlying lysosomal dysfunction in the cortex and hippocampi, key structures involved in learning and memory, of a type 2 diabetes (T2D) mouse model, the leptin receptor deficient db/db mouse. We demonstrate for the first time that diabetes leads to destabilization of lysosomes as well as alterations in the protein expression, activity, and/or trafficking of two lysosomal enzymes, hexosaminidase A and cathepsin D, in the hippocampus of db/db mice. Pioglitazone, a thiazolidinedione (TZD) commonly used in the treatment of diabetes due to its ability to improve insulin sensitivity and reverse hyperglycemia, was ineffective in reversing the diabetes-induced changes on lysosomal enzymes. Our previous work revealed that pioglitazone does not reverse hypercholesterolemia; thus, we investigated whether cholesterol plays a role in diabetes-induced lysosomal changes. In vitro, cholesterol promoted the destabilization of lysosomes, suggesting that lysosomal-related changes associated with diabetes are due to elevated levels of cholesterol. Since lysosome dysfunction precedes neurodegeneration, cognitive deficits, and Alzheimer's disease neuropathology, our results may provide a potential mechanism that links diabetes with complications of the central nervous system.
Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
Name of substance:0 (Thiazolidinediones); 97C5T2UQ7J (Cholesterol); EC 3.2.1.52 (Hexosaminidase A); EC 3.4.23.5 (Cathepsin D); IY9XDZ35W2 (Glucose); X4OV71U42S (pioglitazone)


  4 / 380 MEDLINE  
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PMID:25896637
Author:Osher E; Fattal-Valevski A; Sagie L; Urshanski N; Sagiv N; Peleg L; Lerman-Sagie T; Zimran A; Elstein D; Navon R; Valevski A; Stern N
Address:Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. esteros@tlvmc.gov.il.
Title:Effect of cyclic, low dose pyrimethamine treatment in patients with Late Onset Tay Sachs: an open label, extended pilot study.
Source:Orphanet J Rare Dis; 10:45, 2015 Apr 17.
ISSN:1750-1172
Country of publication:England
Language:eng
Abstract:BACKGROUND: Late Onset Tay- Sachs disease (LOTS) is a rare neurodegenerative lysosomal storage disease which results from mutations in the gene encoding the α subunit (HEXA) of ß-hexosaminidase enzyme (HexA). At the present time, no effective treatment exists for LOTS and other neurodegenerative diseases involving the central nerve system (CNS). Pyrimethamine (PMT) was previously shown to act as a HexA chaperone in human fibroblasts in vitro carrying some (e.g., αG269S), but not all LOTS-related mutations. The present study assessed the effect of cyclic, low dose and long term pyrimethamine treatment on HexA in subjects with LOTS. METHODS: In an open label trial in 4 LOTS patients, PMT was initiated at an average daily dose of ~2.7 mg and administered cyclically guided by blood lymphocyte HexA activity for a mean duration of 82.8 (±22.5; SD) weeks (~1.5 year). RESULTS: HexA activity rose in all subjects, with a mean peak increase of 2.24 folds (±0.52; SD) over baseline activity (range 1.87-3). The mean treatment time required to attain this peak was of 15.7 (±4.8; SD) weeks. Following increase in activity, HexA gradually declined with the continued use of PMT, which was then stopped, resulting in the return of HexA activity to baseline. A second cycle of PMT treatment was then initiated, resulting again in an increase in HexA activity. Three of the patients experienced a measurable neuropsychiatric deterioration whereas one subject remained entirely stable. CONCLUSIONS: Cyclic low dose of PMT can increase HexA activity in LOTS patients. However, the observed increase is repeatedly transient and not associated with discernible beneficial neurological or psychiatric effects.
Publication type:CLINICAL TRIAL; JOURNAL ARTICLE
Name of substance:EC 3.2.1.52 (Hexosaminidase A); Z3614QOX8W (Pyrimethamine)


  5 / 380 MEDLINE  
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PMID:25736958
Author:Sanderson AB; Novak JC; Nash SM; Kolb SJ; Kissel JT
Address:Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Title:Laboratory evaluation of suspected motor neuron disease: A survey of physicians.
Source:Muscle Nerve; 52(1):83-7, 2015 Jul.
ISSN:1097-4598
Country of publication:United States
Language:eng
Abstract:INTRODUCTION: The clinical diagnosis of amyotrophic lateral sclerosis (ALS) relies on exclusion of mimic syndromes, but there are no specific guidelines regarding the extent of laboratory testing required. METHODS: A survey was sent to 274 physicians listed in the Neuromuscular Section of the American Academy of Neurology. The survey asked how often they order 21 different laboratory tests in patients suspected of having ALS. RESULTS: Ninety-nine responses were received (36% response rate). Greater than 75% ordered serum creatine kinase, chemistry panel, and thyroid functions often or always. Fewer than 25% tested for serum complement, hexosaminidase A, spinal muscular atrophy, Kennedy disease, heavy metals, or human T-cell lymphotrophic virus often or always. Twelve other tests had intermediate responses. CONCLUSIONS: There is a lack of consensus among respondents regarding the laboratory evaluation of suspected ALS. Prospective studies are needed to define the diagnostic yield and cost-effectiveness of laboratory testing in this population.
Publication type:JOURNAL ARTICLE
Name of substance:EC 2.7.3.2 (Creatine Kinase); EC 3.2.1.52 (Hexosaminidase A)


  6 / 380 MEDLINE  
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PMID:25441385
Author:Forster CS
Address:Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.
Title:50 Years ago in the Journal of Pediatrics: the startle response and serum enzyme profile in early detection of Tay-Sachs' disease.
Source:J Pediatr; 165(5):944, 2014 Nov.
ISSN:1097-6833
Country of publication:United States
Language:eng
Publication type:HISTORICAL ARTICLE; JOURNAL ARTICLE
Name of substance:EC 3.2.1.52 (Hexosaminidase A)


  7 / 380 MEDLINE  
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PMID:24915922
Author:Huang Y; Xie T; Zheng J; Zhao X; Liu H; Liu L
Address:Department of Endocrinology and Metabolism, Guangzhou Women and Children's Medical Center, Guangzhou 510623, China.
Title:[Clinical and molecular characteristics of a child with juvenile Sandhoff disease].
Source:Zhonghua Er Ke Za Zhi; 52(4):313-6, 2014 Apr.
ISSN:0578-1310
Country of publication:China
Language:chi
Abstract:OBJECTIVE: To explore the clinical features and molecular mutation of HEXB gene in a case with juvenile Sandhoff disease. METHOD: We retrospectively reviewed the clinical, neuroimaging and biochemical findings in this Chinese child with juvenile Sandhoff disease. Hexosaminidase A and hexosaminidase A & B activities were measured in blood leukocytes by fluorometric assay. HEXB gene molecular analysis was performed by PCR and direct sequencing. RESULT: The 9-year-old boy was admitted for psychomotor regression. He presented slowly progressive gait disorder and dysarthria during the last three years. Cranial MRI revealed a marked cerebellar atrophy with normal intensity in the thalamus and basal ganglia. Brain MRS showed normal in the thalamus and basal ganglia. Hexosaminidase A was 69.5 (mg·h) [normal controls 150-360 nmol/(mg·h)], hexosaminidase A & B activity was 119 nmol/(mg·h)[normal controls 600-3 500 nmol/(mg·h)], confirming the diagnosis of Sandhoff disease. The patient was a compound heterozygote for a novel deletion mutation c.1404delT (p. P468P fsX62) and a reported mutation c.1509-26G>A. CONCLUSION: The clinical features of juvenile Sandhoff disease include ataxia, dysarthria and cerebellar atrophy. The enzyme assay and molecular analysis of HEXB gene can confirm the diagnosis of Sandhoff disease. The novel mutation c.1404delT(p. P468P fsX62) is a disease-related mutation.
Publication type:CASE REPORTS; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Name of substance:EC 3.2.1.52 (HEXB protein, human); EC 3.2.1.52 (Hexosaminidase A); EC 3.2.1.52 (Hexosaminidase B); EC 3.2.1.52 (beta-Hexosaminidase beta Chain)


  8 / 380 MEDLINE  
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PMID:24484945
Author:Chojnowska S; Minarowska A; Waszkiewicz N; Kepka A; Zalewska-Szajda B; Goscik E; Kowal K; Olszewska E; Konarzewska-Duchnowska E; Minarowski L; Zwierz K; Ladny JR; Szajda SD
Address:Medical Institute, College of Computer Science and Business Administration, Lomza, Poland. Electronic address: schojnowska@pwsip.edu.pl.
Title:The activity of N-acetyl-ß-d-hexosaminidase A and B and ß-glucuronidase in nasal polyps and hypertrophic nasal concha.
Source:Otolaryngol Pol; 68(1):20-4, 2014 Jan-Feb.
ISSN:2300-8423
Country of publication:Poland
Language:eng
Abstract:UNLABELLED: Nasal polyps and hypertrophic lower nasal conchae are common disorders of nasal cavity. The majority of etiopathogenetic theories indicate inflammatory background of polyps and hypertrophic concha. N-acetyl-ß-D-hexosaminidase and ß-glucuronidase are lysosomal exoglycosidases revealing accelerated activity in inflammatory processes. AIM: The aim of the study was to evaluate the catabolism of glycoconjugates in nasal polyps and hypertrophic nasal concha basing on the activity of N-acetyl-ß-D-hexosaminidase (HEX) and ß-glucuronidase (GLU). MATERIAL AND METHODS: Material consisted of nasal polyps taken from 40 patients during polypectomy in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and hypertrophic lower nasal conchae taken from 20 patients during mucotomy. The activity of HEX, HEX A, HEX B and GLU in supernatant of homogenates of nasal polyps and hypertrophic lower nasal concha tissues has been estimated using colorimetric method. RESULTS: Statistically significant decrease has been observed in concentration of the activity (per 1mg of tissue) of HEX (p<0.05), HEX B (p<0.001) and specific activity (per 1mg of protein) of HEX B (p<0.001) in nasal polyps tissue in comparison to hypertrophic lower nasal conchae tissue. CONCLUSIONS: Decrease in the activity and specific activity concentration of the majority of examined lysosomal exoglycosidases (increasing in inflammations) in comparison to hypertrophic lower nasal conchae suggests electrolytes disorders and questions the inflammatory background of nasal polyps.
Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Name of substance:EC 3.2.1.31 (Glucuronidase); EC 3.2.1.52 (Hexosaminidase A); EC 3.2.1.52 (Hexosaminidase B)


  9 / 380 MEDLINE  
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PMID:24288426
Author:Waszkiewicz N; Zalewska-Szajda B; Chojnowska S; Szajda SD; Zalewska A; Konarzewska B; Szulc A; Wojtulewska-Supron A; Kepka A; Knas M; Ladny JR; Milewski R; Zwierz K
Address:Department of Psychiatry, Medical University of Bialystok, Plac Brodowicza 1, 16-070 Choroszcz, Poland.
Title:The salivary ß-HEX A% index as an excellent marker of periodontitis in smoking alcohol-dependent persons.
Source:Dis Markers; 35(5):457-63, 2013.
ISSN:1875-8630
Country of publication:United States
Language:eng
Abstract:BACKGROUND: Severe periodontitis leading to tooth loss is found in 5-15% of most populations worldwide. AIM: The applicability of salivary ß -hexosaminidase (ß-HEX A%, percentage of ß-HEX A isoenzyme to total ß-HEX) and ß-HEX B% (ß-HEX B/ß-HEX) indexes was investigated as a possible marker of periodontitis. METHODS: Thirty three alcohol-dependent smokers (AS) and 32 healthy controls (C) were enrolled in the study. The activity of ß-HEX was measured spectrophotometrically. RESULTS: ß-HEX A% was significantly higher and ß-HEX B% was lower in AS than in C group. We found a significant correlation between ß-HEX A% and gingival index (GI) and an inverse correlation between ß-HEX A% and salivary flow (SF), in all groups. Salivary ß-HEX A% index in smoking alcoholics at 0.23 had excellent sensitivity (96%) and specificity (91%); the AUC for ß-HEX A% was high (0.937). There were no correlations between amount/duration-time of alcohol drinking/smoking and ß-HEX A% or ß-HEX B%. We found significant correlations between the time period of denture wearing and GI, papilla bleeding index (PBI), and decayed missing filled teeth index (DMFT) and between GI and the amount of smoked cigarettes per day. CONCLUSION: Bad periodontal state was most likely due to the nicotine dependence. Salivary ß-HEX A% is a promising excellent marker for the diagnosis of periodontitis.
Publication type:JOURNAL ARTICLE
Name of substance:0 (Biomarkers); EC 3.2.1.52 (Hexosaminidase A)


  10 / 380 MEDLINE  
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PMID:23894776
Author:Raczkowska K; Zalewska-Szajda B; Chojnowska S; Kepka A; Raczkowski K; Waszkiewicz N; Siedlecka-Czykier E; Dadan J; Snarska J; Zwierz K; Ladny JR; Szajda SD
Address:Wyzsza Szkola Zawodowa Ochrony Zdrowia Towarzystwa Wiedzy Powszechnej w Lomzy. kasied@o2.pl
Title:Izoenzymy A i B lizosomalnej N-acetylo-beta-D-heksozoaminidazy w surowicy i moczu chorych zywionych pozajelitowo. [Isoforms A and B of lysosomal N-acetyl-beta-D-hexosaminidase in serum and urine of parenterally fed patients].
Source:Pol Merkur Lekarski; 34(203):259-62, 2013 May.
ISSN:1426-9686
Country of publication:Poland
Language:pol
Abstract:UNLABELLED: Parenteral nutrition entails numerous metabolic complications resulting from food bypass of the gastrointestinal tract. Up to now have not been established all complications of parenteral nutrition, despite intensive research and clinical observations. Knowledge of the biochemical changes resulting from parenteral nutrition is essential to effective prevention, early detection and effective treatment of the metabolic disorders induced by parenteral nutrition. The aim of the study was to evaluate the catabolism of glycoconjugates of parenterally fed patients, reflected by the activity of N-acetyl-beta-D-hexosaminidase (HEX): HEX A and HEX B isoenzymes in serum and urine. MATERIAL AND METHODS: Samples of blood and urine were collected from 23 patients: before intravenous alimentation, at start, as well as of fifth and tenth day of parenteral nutrition. The activity of HEX A and HEX B in serum and urine was determined by the colorimetric method of Zwierz et al. as modified by Marciniak et al. The activity of urinary HEXA and HEX B has been calculated per 1 mg of creatinine. RESULTS: The activity of serum HEXA significantly decreased at fifth day, in comparison to the activity before parenteral alimentation, and significantly increased at tenth day of parenteral nutrition. The activity of HEX B in serum increased significantly at fifth and tenth day of the parenteral nutrition. CONCLUSIONS: Parenteral nutrition alter the catabolism of glycoconjugates, reflected by significant changes in serum HEX A and HEX B activities. Urine was the not appropriate material to evaluate the catabolism of glycoconjugates in view of HEX A and HEX B activities.
Publication type:ENGLISH ABSTRACT; JOURNAL ARTICLE
Name of substance:EC 3.2.1.52 (Hexosaminidase A); EC 3.2.1.52 (Hexosaminidase B)



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