Arylsulfatase G inactivation causes loss of heparan sulfate 3-O-sulfatase activity and mucopolysaccharidosis in mice

Deficiency of glycosaminoglycan (GAG) degradation causes a subclass of lysosomal storage disorders called mucopolysaccharidoses (MPSs), many of which present with severe neuropathology. Critical steps in the degradation of the GAG heparan sulfate remain enigmatic. Here we show that the lysosomal ary...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-06, Vol.109 (26), p.10310-10315
Main Authors: Kowalewski, Björn, Lamanna, William C, Lawrence, Roger, Damme, Markus, Stroobants, Stijn, Padva, Michael, Kalus, Ina, Frese, Marc-André, Lübke, Torben, Lüllmann-Rauch, Renate, D’Hooge, Rudi, Esko, Jeffrey D, Dierks, Thomas
Format: Article
Language:English
Subjects:
animal organs
Animals
Apoptosis
arylsulfatase
Arylsulfatases - antagonists & inhibitors
Behavior, Animal
Biological Sciences
cell death
central nervous system
Enzymes
Heparan sulfate
humans
Kidneys
Liver
Metabolic diseases
Metachromatic leukodystrophy
Mice
Mucopolysaccharidoses
Mucopolysaccharidoses - enzymology
Mucopolysaccharidoses - etiology
mucopolysaccharidosis
Nervous system
Nervous system diseases
Neurons
neuropathology
Rodents
Sulfatases - metabolism
Sulfates
Vacuoles
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Summary:Deficiency of glycosaminoglycan (GAG) degradation causes a subclass of lysosomal storage disorders called mucopolysaccharidoses (MPSs), many of which present with severe neuropathology. Critical steps in the degradation of the GAG heparan sulfate remain enigmatic. Here we show that the lysosomal arylsulfatase G (ARSG) is the long-sought glucosamine-3- O -sulfatase required to complete the degradation of heparan sulfate. Arsg -deficient mice accumulate heparan sulfate in visceral organs and the central nervous system and develop neuronal cell death and behavioral deficits. This accumulated heparan sulfate exhibits unique nonreducing end structures with terminal N -sulfoglucosamine-3- O -sulfate residues, allowing diagnosis of the disorder. Recombinant human ARSG is able to cleave 3- O -sulfate groups from these residues as well as from an authentic 3- O -sulfated N -sulfoglucosamine standard. Our results demonstrate the key role of ARSG in heparan sulfate degradation and strongly suggest that ARSG deficiency represents a unique, as yet unknown form of MPS, which we term MPS IIIE.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1202071109