Storage of lipofuscin in neurons in mucopolysaccharidosis

Oldfors, Anders; Sourander, Patrick

doi:10.1007/bf00697002

Cited by 27 publications

(2 citation statements)

References 22 publications

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“…Ceroid- and lipofuscin cytoplasmic and lysosomal inclusions within the brain emit autofluorescent (AF) signals in a broad wavelength spectrum that can be detected by epifluorescence microscopy [[51], [52]]. The AF load in brain is increased in MPS pathology and MPS IIIA mice, being located mainly in neurons [30,47].…”

Section: Resultsmentioning

confidence: 99%

“…The antibody used detected both endogenous sulfamidase and CM-rhSulfamidase, but in MPS IIIA mice these endogenous levels are low (undetectable). Cytoplasmic compartments of neurons including lysosomes can be identified by autofluorescence from the cerebral cortex of MPS III mice and patients [27],31,36]. Indirect evidence that CM-rhSulfamidase reached the target compartment in brain, was its co-localization with the autofluorescing cytoplasmic inclusions.…”

Section: Discussionmentioning

confidence: 99%

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Intravenous delivery of a chemically modified sulfamidase efficiently reduces heparan sulfate storage and brain pathology in mucopolysaccharidosis IIIA mice

Gustavsson

Sjöström

Tjernberg

et al. 2019

Molecular Genetics and Metabolism Reports

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Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder (LSD) characterized by severe central nervous system (CNS) degeneration. The disease is caused by mutations in the SGSH gene coding for the lysosomal enzyme sulfamidase. Sulfamidase deficiency leads to accumulation of heparan sulfate (HS), which triggers aberrant cellular function, inflammation and eventually cell death. There is currently no available treatment against MPS IIIA. In the present study, a chemically modified recombinant human sulfamidase (CM-rhSulfamidase) with disrupted glycans showed reduced glycan receptor mediated endocytosis, indicating a non-receptor mediated uptake in MPS IIIA patient fibroblasts. Intracellular enzymatic activity and stability was not affected by chemical modification. After intravenous (i.v.) administration in mice, CM-rhSulfamidase showed a prolonged exposure in plasma and distributed to the brain, present both in vascular profiles and in brain parenchyma. Repeated weekly i.v. administration resulted in a dose- and time-dependent reduction of HS in CNS compartments in a mouse model of MPS IIIA. The reduction in HS was paralleled by improvements in lysosomal pathology and neuroinflammation. Behavioral deficits in the MPS IIIA mouse model were apparent in the domains of exploratory behavior, neuromuscular function, social- and learning abilities. CM-rhSulfamidase treatment improved activity in the open field test, endurance in the wire hanging test, sociability in the three-chamber test, whereas other test parameters trended towards improvements. The unique properties of CM-rhSulfamidase described here strongly support the normalization of clinical symptoms, and this candidate drug is therefore currently undergoing clinical studies evaluating safety and efficacy in patients with MPS IIIA.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Intravenous delivery of a chemically modified sulfamidase efficiently reduces heparan sulfate storage and brain pathology in mucopolysaccharidosis IIIA mice

Gustavsson

Sjöström

Tjernberg

et al. 2019

Molecular Genetics and Metabolism Reports

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Comparative biology of the neuronal ceroid‐lipofuscinoses (NCL): An overview

Jolly

1995

Am. J. Med. Genet.

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Multiple forms of ceroid-lipofuscinosis occur in human beings and animals. They are characterized by brain and retinal atrophy associated with selective necrosis of neurons. This neurodegenerative disease appears associated with the disease process rather than storage of fluorescent lipopigment per se, and there is now growing evidence that pathogenesis may involve mitochondria rather than a primary defect of lysosomal catabolism. Of the forms of ceroid-lipofuscinosis studied, most but not all reflect accumulation of subunit c of mitochondrial ATP synthase. If there is a common denominator between all forms other than the presence of fluorescent lipopigment, then it may be the accumulation of hydrophobic protein. Analogous diseases in animals can be expected to reflect the same spectrum of biochemical changes, and they warrant in-depth study to help understand the pathogenesis and heterogeneity of the group.

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Abnormal Lipopigments and Lysosomal Residual Bodies in Metachromatic Leukodystrophy

Hh¹,

Busch²

1990

Lipofuscin and Ceroid Pigments

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Storage of lipofuscin in neurons in mucopolysaccharidosis

Cited by 27 publications

References 22 publications

Intravenous delivery of a chemically modified sulfamidase efficiently reduces heparan sulfate storage and brain pathology in mucopolysaccharidosis IIIA mice

Intravenous delivery of a chemically modified sulfamidase efficiently reduces heparan sulfate storage and brain pathology in mucopolysaccharidosis IIIA mice

Comparative biology of the neuronal ceroid‐lipofuscinoses (NCL): An overview

Abnormal Lipopigments and Lysosomal Residual Bodies in Metachromatic Leukodystrophy

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