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Arylsulfatase A (ARSA) is a lysosomal enzyme implicated in most cases of metachromatic leukodystrophy (MLD). The quaternary structure of ARSA is pH-dependent: at neutral pH, ARSA is a homodimeric protein; at lysosomal (acidic) pH, ARSA is homo-octameric. This dimer–octamer transition seems to be of major importance for the stability of the enzyme in the lysosomal milieu. Sedimentation analysis was used to study the oligomerization capacity of C300F and P425T-substituted ARSA, two MLD-associated forms of the enzyme displaying reduced lysosomal half-lives. P425T-ARSA displays a modest reduction in its octamerization capacity. In contrast, the C300F mutation strongly interferes with the octamerization process of ARSA but not with its dimerization capacity. Interestingly, a major fraction of dimeric ARSA-C300F is composed of covalently linked ARSA molecules, through a thiol-cleavable bond that probably involves Cys414 residues from each monomer. Our data support the notion that the reduced lysosomal half-life of some mutated forms of ARSA is related to deficient octamerization. [Copyright &y& Elsevier]

Arylsulfatase A pseudodeficiency (ARSA-PD) may be related to increased susceptibility to neuro-psychiatric disorders. An association of allele 2417G/3352A with schizophrenia was found in a group of Portuguese patients. In the Portuguese population, at least one PD associated alteration exists in 18.3% of the ARSA alleles. Allele 2417G/3352G was invariably associated with a conserved haplotype, while 2417G/3352A and the rare 2417A/3352G alleles appeared on different haplotypes. [Copyright &y& Elsevier]