Disease relevance of Arsa

• Phenotype of arylsulfatase A-deficient mice: relationship to human metachromatic leukodystrophy [1].
• Metachromatic leukodystrophy is a lysosomal sphingolipid storage disorder caused by the deficiency of arylsulfatase A. The disease is characterized by progressive demyelination, causing various neurologic symptoms [1].
• Arylsulfatase A (ASA)-deficient mice constitute an animal model for the inherited lysosomal storage disease, metachromatic leukodystrophy (MLD) [2].
• The hyperactivity, motor incoordination and slowing, and the age-related learning/memory defects, reported here in ASA-deficient mice, may relate to the decline of neuromotor and cognitive functions in MLD patients, and could be used as correlative or outcome measures in the study of MLD pathophysiology and treatment [3].
• The activities of arylsulfatase A and B from transplanted carcinomas with four histological types were more than twofold higher as compared to those from surgical tumors, except for arylsulfatase A activity in blastoma [4].

High impact information on Arsa

• Metachromatic leukodystrophy (MLD) is a lipidosis caused by deficiency of arylsulfatase A (ARSA) [5].
• By transplanting HSCs transduced with the arylsulfatase A gene, we fully reconstituted enzyme activity in the hematopoietic system of MLD mice and prevented the development of motor conduction impairment, learning and coordination deficits, and neuropathological abnormalities typical of the disease [6].
• However, the degradation of the endocytosed index protein arylsulfatase A was strongly reduced in all of the mutant CLN6 cell lines compared with controls [7].
• Translational control of arylsulfatase A expression in mouse testis [8].
• High levels of arylsulfatase A mRNA are found in germ cells of mouse testis [8].

Chemical compound and disease context of Arsa

• A deficiency of arylsulfatase A (ASA) causes the lysosomal storage disease metachromatic leukodystrophy, which is characterized by accumulation of the sphingolipid 3-O-sulfogalactosylceramide (sulfatide) [9].
• Arylsulfatase A, arylsulfatase B, and arylsulfatase Bv, in both normal liver and granulomas, were separated by anion-exchange column chromatography and differences in net charges of these enzymes were demonstrated by polyacrylamide gel electrophoresis [10].
• Coexpression of formylglycine-generating enzyme is essential for synthesis and secretion of functional arylsulfatase A in a mouse model of metachromatic leukodystrophy [11].
• Sulphatide (cerebroside sulphate) metabolism of C3H/He mouse kidney was investigated in the course of compensatory renal hypertrophy in association with the change of [Na+,K+]-dependent ATPase, arylsulfatase A and beta-galactosidase activity [12].

Biological context of Arsa

• Both vectors harbor the human ASA cDNA controlled by the retroviral promoter/enhancer element, but differ by the presence or absence of a neomycin resistance gene driven by an internal promoter [13].
• This hypothesis was supported by our results revealing the presence of AS-A in the epididymal and vas deferens fluid (determined by immunoblotting and ELISA) and an AS-A transcript in the epididymis (by reverse transcription polymerase chain reaction) [14].
• Brainstem auditory-evoked potentials (BAEPs) were recorded in control and ASA-deficient mice of 3, 6, 9 and 12 months [2].
• Histological examination and morphometric analysis showed that the decline of BAEPs in ASA (-/-) mice was paralleled by a decrease in spiral ganglion cell numbers [2].
• The latter enzyme was thermostable, resistant to inhibition by silver, completely inhibited by phosphate, displayed linear kinetics, and had a higher pH optimum than arylsulfatase A. Anionic arylsulfatase B also hydrolyzed chondroitin-4-SO4 heptasaccharide [15].

Anatomical context of Arsa

• To establish gene therapy protocols for ASA-deficient mice, we constructed two retroviral vectors based on the murine stem cell virus [13].
• A comparative analysis of the one- versus the two-gene vector and an amphotropic versus an ecotropic producer cell line revealed that the amphotropic producer cell line for the one-gene vector transfers ASA overexpression to the target cells most efficiently [13].
• A deficiency of arylsulfatase A (ASA) causes the lysosomal storage disease metachromatic leukodystrophy (MLD) which is characterized primarily by demyelination of the central nervous system [13].
• In contrast, positive AS-A staining was observed in the heads of live caudal epididymal and vas deferens sperm [14].
• Immunocytochemistry of the epididymis revealed AS-A in narrow and apical cells in the initial segment and in clear cells in all epididymal regions [14].

Associations of Arsa with chemical compounds

• Transplanted MLD mice had reduced sulfatide accumulation in the CNS, increased brain ARSA activity, and full prevention of the electrophysiological and motor deficits that characterize untreated MLD mice [16].
• Rodent arylsulfatase A activity was grossly underestimated when 4-methyl-umbelliferyl sulfate was employed as substrate [15].
• Rodent and bovine arylsulfatase B hydrolyze 4-methylumbelliferyl sulfate (4MUS) 10- to 30-fold more efficiently than arylsulfatase A. Therefore, 4MUS grossly underestimates arylsulfatase A activity in the presence of excess arylsulfatase B [17].
• The correct intracellular sorting of lysosomal enzymes such as arylsulfatase A depends on the presence of mannose 6-phosphate residues on high mannose type oligosaccharides [18].
• Reduced brain cholesterol content in arylsulfatase A-deficient mice [19].

Other interactions of Arsa

• Recordings of unitary potentials and stimulation of climbing fibers on cerebellar slices from 2-year-old mice indicated that, although the main cerebellar synapses seem to be present and functioning physiologically, the climbing fibers of ASA-deficient mice may have enhanced effects on Purkinje cell activity [20].
• One-year-old ASA(-/-) mice showed impaired rotarod performance and altered walking pattern characterized by a shorter pace, later evolving into more severe ataxia with tremor in 2-year-old mice [20].
• The enzymatic activity of five acid hydrolases: acid phosphatase, arylsulfatase A, deoxyribonuclease, beta-glucuronidase, and cathepsin D, was assayed in fetal (fifteenth and eighteenth days of pregnancy) and neonatal (Days 0, 5, 10, and 15 post-partum) mouse liver [21].
• Age-related changes in cerebroside sulfotransferase (measured in brain) and arylsulfatase A and cerebroside B-galactosidase (measured in brain and liver) were the same for shiverer and control mice [22].
• The developmental patterns and the activities of arylsulfatase A were, however, normal in the cerebrum and cerebellum of jimpy mice [23].

Analytical, diagnostic and therapeutic context of Arsa

• Since no naturally occurring animal model of the disease is available, we have generated arylsulfatase A-deficient mice [1].
• To assess the therapeutic potential of enzyme replacement therapy (ERT), ASA knockout mice were treated by intravenous injection of recombinant human ASA [9].
• The entire ARSA cDNA has been cloned by PCR from reverse-transcribed RNA [24].
• However, immunofluorescence and flow cytometry indicated the absence of AS-A on the surface of live testicular sperm [14].
• Motor coordination and equilibrium, as tested in the rotarod test, was impaired in 12-month-old ASA-deficient mice [3].

References