scholarly journals Competitive binding of extracellular accumulated heparan sulfate reduces lysosomal storage defects and triggers neuronal differentiation in a model of Mucopolysaccharidosis IIIB

2021 ◽  
pp. 119113
Author(s):  
Valeria De Pasquale ◽  
Gianluca Scerra ◽  
Melania Scarcella ◽  
Massimo D’Agostino ◽  
Luigi Michele Pavone
Keyword(s):  
Heparan Sulfate ◽  
Neuronal Differentiation ◽  
Competitive Binding ◽  
Lysosomal Storage

scholarly journals Altered heparan sulfate metabolism during development triggers dopamine-dependent autistic-behaviours in models of lysosomal storage disorders

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Maria De Risi ◽  
Michele Tufano ◽  
Filomena Grazia Alvino ◽  
Maria Grazia Ferraro ◽  
Giulia Torromino ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Sch 23390 ◽  
Lysosomal Storage Disorders ◽  
Dopamine Neurons ◽  
Therapeutic Effects ◽  
Lysosomal Storage ◽  
Cellular Models ◽  
Mps Ii ◽  
Mps Iiia ◽  
Storage Disorders

AbstractLysosomal storage disorders characterized by altered metabolism of heparan sulfate, including Mucopolysaccharidosis (MPS) III and MPS-II, exhibit lysosomal dysfunctions leading to neurodegeneration and dementia in children. In lysosomal storage disorders, dementia is preceded by severe and therapy-resistant autistic-like symptoms of unknown cause. Using mouse and cellular models of MPS-IIIA, we discovered that autistic-like behaviours are due to increased proliferation of mesencephalic dopamine neurons originating during embryogenesis, which is not due to lysosomal dysfunction, but to altered HS function. Hyperdopaminergia and autistic-like behaviours are corrected by the dopamine D1-like receptor antagonist SCH-23390, providing a potential alternative strategy to the D2-like antagonist haloperidol that has only minimal therapeutic effects in MPS-IIIA. These findings identify embryonic dopaminergic neurodevelopmental defects due to altered function of HS leading to autistic-like behaviours in MPS-II and MPS-IIIA and support evidence showing that altered HS-related gene function is causative of autism.

scholarly journals Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches

2020 ◽  
Vol 21 (21) ◽  
pp. 7819
Author(s):  
Noelia Benetó ◽  
Lluïsa Vilageliu ◽  
Daniel Grinberg ◽  
Isaac Canals
Keyword(s):  
Heparan Sulfate ◽  
Disease Modeling ◽  
Neuronal Degeneration ◽  
Lysosomal Storage ◽  
Sanfilippo Syndrome ◽  
Therapeutic Approaches ◽  
Cellular Mechanisms ◽  
Cellular Models ◽  
Induced Pluripotent ◽  
Cellular Dysfunction

Sanfilippo syndrome or mucopolysaccharidosis III is a lysosomal storage disorder caused by mutations in genes responsible for the degradation of heparan sulfate, a glycosaminoglycan located in the extracellular membrane. Undegraded heparan sulfate molecules accumulate within lysosomes leading to cellular dysfunction and pathology in several organs, with severe central nervous system degeneration as the main phenotypical feature. The exact molecular and cellular mechanisms by which impaired degradation and storage lead to cellular dysfunction and neuronal degeneration are still not fully understood. Here, we compile the knowledge on this issue and review all available animal and cellular models that can be used to contribute to increase our understanding of Sanfilippo syndrome disease mechanisms. Moreover, we provide an update in advances regarding the different and most successful therapeutic approaches that are currently under study to treat Sanfilippo syndrome patients and discuss the potential of new tools such as induced pluripotent stem cells to be used for disease modeling and therapy development.

scholarly journals LAR-RPTP Clustering Is Modulated by Competitive Binding between Synaptic Adhesion Partners and Heparan Sulfate

2017 ◽  
Vol 10 ◽  
Author(s):  
Seoung Youn Won ◽  
Cha Yeon Kim ◽  
Doyoun Kim ◽  
Jaewon Ko ◽  
Ji Won Um ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Competitive Binding

scholarly journals Elevated LysoGb3 Concentration in the Neuronopathic Forms of Mucopolysaccharidoses

Diagnostics ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 155 ◽  
Author(s):  
Galina Baydakova ◽  
Alex Ilyushkina ◽  
Lidia Gaffke ◽  
Karolina Pierzynowska ◽  
Igor Bychkov ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Fabry Disease ◽  
Direct Result ◽  
Control Group ◽  
Lysosomal Storage ◽  
Mps Ii ◽  
Mps Vi ◽  
Mps I ◽  
Mps Iii

Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders associated with impaired glycosaminoglycans (GAGs) catabolism. In MPS I, II, III, and VII, heparan sulfate (HS) cannot be degraded because of the lack of sufficient activity of the respective enzymes, and its accumulation in the brain causes neurological symptoms. Globotriaosylsphingosine (LysoGb3), the deacylated form of globotriaosylceramide (Gb3), is described as a highly sensitive biomarker for another lysosomal storage disease—Fabry disease. The connection between MPSs and LysoGb3 has not yet been established. This study included 36—MPS I, 15—MPS II, 25—MPS III, 26—MPS IV, and 14—MPS VI patients who were diagnosed by biochemical and molecular methods and a control group of 250 males and 250 females. The concentration of lysosphingolipids (LysoSLs) was measured in dried blood spots by high pressure liquid chromatography—tandem mass spectrometry. We have demonstrated that LysoGb3 concentration was significantly elevated (p < 0.0001) in untreated MPS I (3.07 + 1.55 ng/mL), MPS II (5.24 + 2.13 ng/mL), and MPS III (6.82 + 3.69 ng/mL) patients, compared to the control group (0.87 + 0.55 ng/mL). LysoGb3 level was normal in MPS VI and MPS IVA (1.26 + 0.39 and 0.99 + 0.38 ng/mL, respectively). Activity of α-galactosidase A (α-Gal A), an enzyme deficient in Fabry disease, was not, however, inhibited by heparan sulfate in vitro, indicating that an increase of LysoGb3 level in MPS I, MPS II, and MPS III is an indirect effect of stored MPSs rather than a direct result of impairment of degradation of this compound by HS. Our findings indicate some association of elevated LysoGb3 concentration with the neuronopathic forms of MPSs. The pathological mechanism of which is still to be studied.

scholarly journals Assumption of heparin-induced thrombocytopenia in mucopolysaccharidoses

2021 ◽  
Vol 4 (3) ◽  
pp. 419-422
Author(s):  
Liliya Aleksandrovna Osipova ◽  
Lyudmila Mikhailovna Kuzenkova
Keyword(s):  
Heparan Sulfate ◽  
Blood Count ◽  
Complete Blood Count ◽  
Lysosomal Storage Diseases ◽  
Cross Sectional Study ◽  
P Value ◽  
Lysosomal Storage ◽  
Cross Sectional ◽  
Female Ratio ◽  
Mps I

Background: Mucopolysaccharidoses (MPSs) are a group of lysosomal storage diseases, resulted from glycosaminoglycans’ breakdown failure (GAGs). The study aims to determine the presence of thrombocytopenia, its prevalence, clinical implication, and correlation with the types of MPSs and with the types of glycosaminoglycans storage. Methods: A retrospective cross-sectional study of complete blood count data was conducted among 108 children with a confirmed diagnosis of MPS in the National Medical Research Center for Children's Health, Moscow, Russian Federation. STATISTICA 10 (Stat Soft, Inc. 1984-2011) was used for statistical analysis. A p-value of ≤0.05 was considered significant. Results: The median age of children was 65 [IQR: 41; 102] months, range: 3 – 102 months. The male to female ratio was 3:1. The prevalence of fluctuating or persistent thrombocytopenia in all children with MPS was 19.0%. Thrombocytopenia occurred in patients with MPS I (14.0%), II (19.0%), and III (31.0%). Neither of the patients with MPS IV nor VI demonstrated low platelet count. There was a non-significant predominance (P=0.068) of thrombocytopenia frequency in patients with heparan sulfate storage (22.0%) compared with patients without heparan sulfate burden (0%). Conclusion: Routine checkups of patients with MPSs must include complete blood count with platelet measurement. Cases of thrombocytopenia that requiring treatment, immunomodulatory/ immunosuppressive therapy should be considered. Further research is needed to look for the laboratory confirmation of autoimmune variants of HIT in patients with MPS I, II, III.

What Can We Learn from the Parents of Children Affected with Mucopolysaccharidosis Type III-A in Israel?

2021 ◽  
pp. 45-49
Author(s):  
Shiri Liber ◽  
Orna Staretz-Chacham ◽  
Mor Kishon ◽  
Ben Pode-Shakked ◽  
Odelia Chorin ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Clinical Manifestations ◽  
Ethnic Origin ◽  
Global Developmental Delay ◽  
Mucopolysaccharidosis Type ◽  
Lysosomal Storage ◽  
Delay In Diagnosis ◽  
Type Iii ◽  
Mucopolysaccharidosis Type Iii ◽  
Mps Iii

Sanfilippo Syndrome, or mucopolysaccharidosis type III (MPS III), is a group of autosomal-recessive lysosomal storage disorders leading to tissue accumulation of heparan sulfate. MPS III is caused by deficiency in one of 4 enzymes involved in lysosomal degradation of heparan sulfate. Based on the relevant enzyme deficiency, 4 types have been recognized. MPS III constitutes a progressive neurodegenerative and systemic disorder. Parents of children diagnosed with MPS III were interviewed using a retrospective questionnaire based on the known clinical manifestations of MPS III. Eight patients from 4 unrelated families of varied ethnic origin were included. All children were diagnosed with MPS type III-A. Average age at diagnosis was 6.1 years. The most common early clinical manifestations leading to parental suspicion of illness were speech delay and coarse facial features. All children were reported to have global developmental delay, sleep disorders, recurrent infections, hyperactivity, and decreased hearing. The time from first medical inquiry until diagnosis was over 2 years on average, consistent with the delay in diagnosis described in the literature. MPS III children frequently undergo early and repeated ear, nose and throat surgeries, thus we suggest that a high index of suspicion is warranted in relevant clinical circumstances.

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