Heparan sulfate proteoglycans: The sweet side of development turns sour in mucopolysaccharidoses

Pasquale, Valeria De; Pavone, Luigi Michele

doi:10.1016/j.bbadis.2019.165539

Cited by 70 publications

(71 citation statements)

References 153 publications

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“…Given the established role of heparan sulfate proteoglycans in cellular and morphogen signaling in the brain during neurogenesis, axonal guidance and synaptogenesis (reviewed in [136]), it is highly probable that the altered catabolism of this GAG could interfere with these events. Indeed, there is an increasing evidence that the accumulation of highly sulfated oligosaccharides of heparan sulfate in MPS can be particularly deleterious [76,81,137].…”

Section: Specific Effects Of Heparan Sulfatementioning

confidence: 99%

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Héon-Roberts

Nguyen

Pshezhetsky

2020

JCM

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The mucopolysaccharidoses (MPS) are a group of diseases caused by the lysosomal accumulation of glycosaminoglycans, due to genetic deficiencies of enzymes involved in their degradation. MPS III or Sanfilippo disease, in particular, is characterized by early-onset severe, progressive neurodegeneration but mild somatic involvement, with patients losing milestones and previously acquired skills as the disease progresses. Despite being the focus of extensive research over the past years, the links between accumulation of the primary molecule, the glycosaminoglycan heparan sulfate, and the neurodegeneration seen in patients have yet to be fully elucidated. This review summarizes the current knowledge on the molecular bases of neurological decline in Sanfilippo disease. It emerges that this deterioration results from the dysregulation of multiple cellular pathways, leading to neuroinflammation, oxidative stress, impaired autophagy and defects in cellular signaling. However, many important questions about the neuropathological mechanisms of the disease remain unanswered, highlighting the need for further research in this area.

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Section: Specific Effects Of Heparan Sulfatementioning

confidence: 99%

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Héon-Roberts

Nguyen

Pshezhetsky

2020

JCM

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“…In MPSs, the lysosomal accumulation of undigested GAGs is considered the "primum movens" of the subsequent functional cell impairment; however, evidence demonstrates that the accumulation of storage material does not occur only in the lysosomes, but also on the cell surface and ECM where GAGs form proteoglycans through their covalent binding to a core protein [105,106,109]. The accumulation of storage material in non-lysosomal compartments accounts for impaired cell signaling and trafficking, protein unfolding, abnormal autophagy, alterations of intracellular calcium homeostasis, lysolipid accumulation, and modifications in other cellular processes that ultimately lead to the MPS phenotypes [150][151][152][153][154][155][156][157][158][159].…”

Section: Cathepsin Involvement In the Pathophysiology Of Mucopolysaccmentioning

confidence: 99%

“…The accumulation of undigested GAGs in the lysosomes of connective tissue cells and chondrocytes is responsible for musculoskeletal abnormalities commonly observed in almost all MPS subtypes [100][101][102][103][104][105][106][194][195][196]. However, in MPSs, the pathogenesis of the skeletal and joint disease, including growth impairment, may involve complex molecular mechanisms underlying alterations of cartilage and bone metabolism, as well as inflammatory pathways [197].…”

Section: Cathepsin Involvement In the Pathophysiology Of Mucopolysaccmentioning

confidence: 99%

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Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Pasquale

Moles

Pavone

2020

Cells

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Cathepsins (CTSs) are ubiquitously expressed proteases normally found in the endolysosomal compartment where they mediate protein degradation and turnover. However, CTSs are also found in the cytoplasm, nucleus, and extracellular matrix where they actively participate in cell signaling, protein processing, and trafficking through the plasma and nuclear membranes and between intracellular organelles. Dysregulation in CTS expression and/or activity disrupts cellular homeostasis, thus contributing to many human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and others. This review aimed to highlight the involvement of CTSs in inherited lysosomal storage disorders, with a primary focus to the emerging evidence on the role of CTSs in the pathophysiology of Mucopolysaccharidoses (MPSs). These latter diseases are characterized by severe neurological, skeletal and cardiovascular phenotypes, and no effective cure exists to date. The advance in the knowledge of the molecular mechanisms underlying the activity of CTSs in MPSs may open a new challenge for the development of novel therapeutic approaches for the cure of such intractable diseases.

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“…Mucopolysaccharidosis type IIIB (MPS IIIB) is an inherited metabolic disease caused by the deficiency of the enzyme α-N-Acetylglucosaminidase (NAGLU, EC: 3.2.1.50) required for the degradation of the glycosaminoglycan (GAG) heparan sulfate (HS) [1,2]. The undigested HS accumulates in different tissues leading to progressive cellular damage and organ dysfunction, with the central nervous system (CNS) being the primary site of the pathology [3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Proteomic Analysis of Mucopolysaccharidosis IIIB Mouse Brain

et al. 2020

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Mucopolysaccharidosis IIIB (MPS IIIB) is an inherited metabolic disease due to deficiency of α-N-Acetylglucosaminidase (NAGLU) enzyme with subsequent storage of undegraded heparan sulfate (HS). The main clinical manifestations of the disease are profound intellectual disability and neurodegeneration. A label-free quantitative proteomic approach was applied to compare the proteome profile of brains from MPS IIIB and control mice to identify altered neuropathological pathways of MPS IIIB. Proteins were identified through a bottom up analysis and 130 were significantly under-represented and 74 over-represented in MPS IIIB mouse brains compared to wild type (WT). Multiple bioinformatic analyses allowed to identify three major clusters of the differentially abundant proteins: proteins involved in cytoskeletal regulation, synaptic vesicle trafficking, and energy metabolism. The proteome profile of NAGLU−/− mouse brain could pave the way for further studies aimed at identifying novel therapeutic targets for the MPS IIIB. Data are available via ProteomeXchange with the identifier PXD017363.

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Heparan sulfate proteoglycans: The sweet side of development turns sour in mucopolysaccharidoses

Cited by 70 publications

References 153 publications

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Proteomic Analysis of Mucopolysaccharidosis IIIB Mouse Brain

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