Anti-ARSG monoclonal antibody Made to order

Arylsulfatase G (ARSG) is a recently identified lysosomal sulfatase that was shown to be responsible for the degradation of 3-O-sulfated N-sulfoglucosamine residues of heparan sulfate glycosaminoglycans. Deficiency of ARSG leads to a new type of mucopolysaccharidosis, as described in a mouse model. Here, we provide a detailed molecular characterization of the endogenous murine enzyme. ARSG is expressed and proteolytically processed in a tissue-specific manner. The 63-kDa single-chain precursor protein localizes to pre-lysosomal compartments and tightly associates with organelle membranes, most likely the endoplasmic reticulum. In contrast, proteolytically processed ARSG fragments of 34-, 18-, and 10-kDa were found in lysosomal fractions and lost their membrane association. The processing sites and a disulfide bridge between the 18- and 10-kDa chains could be roughly mapped. Proteases participating in the processing were identified as cathepsins B and L. Proteolytic processing is dispensable for hydrolytic sulfatase activity in vitro. Lysosomal transport of ARSG in the liver is independent of mannose 6-phosphate, sortilin, and Limp2. However, mutation of glycosylation site N-497 abrogates transport of ARSG to lysosomes in human fibrosarcoma cells, due to impaired mannose 6-phosphate modification.

Neuronal ceroid lipofuscinoses (NCLs) represent a group of inherited progressive encephalopathies characterized by progressive loss of vision, mental or motor deterioration, epileptic seizures and premature death. A spontaneous canine model of adult American Staffordshire Terriers developing an autosomal recessive NCL has been described. Through a combined genome-wide association and linkage study, a worldwide breed-specific variant in the arylsulfatase G (ARSG) gene was identified. ARSG encodes a lysosomal sulfatase. The variant causes a non-conservative amino-acid substitution in the protein. The missense substitution leads to a 75% sulfatase activity decrease in leucocytes from affected dogs. These results unravel the key role played by ARSG in NCL and neuronal homeostasis and suggest that sulfatase activity might be evaluated in human patients affected by late-onset forms of NCL. Further, a canine genomic predictive DNA-test has been developed to serve the future of the breed.