Topic
Multiple sulfatase deficiency
About: Multiple sulfatase deficiency is a research topic. Over the lifetime, 160 publications have been published within this topic receiving 5924 citations. The topic is also known as: Austin disease & Sulfatidosis, Juvenile, Austin Type.
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TL;DR: Lysosomal storage impairs autophagic delivery of bulk cytosolic contents to lysosomes, identifying LSDs as 'autophagy disorders' and suggesting the presence of common mechanisms in the pathogenesis of these and other neurodegenerative diseases.
Abstract: Most lysosomal storage disorders (LSDs) are caused by deficiencies of lysosomal hydrolases. While LSDs were among the first inherited diseases for which the underlying biochemical defects were identified, the mechanisms from enzyme deficiency to cell death are poorly understood. Here we show that lysosomal storage impairs autophagic delivery of bulk cytosolic contents to lysosomes. By studying the mouse models of two LSDs associated with severe neurodegeneration, multiple sulfatase deficiency (MSD) and mucopolysaccharidosis type IIIA (MPSIIIA), we observed an accumulation of autophagosomes resulting from defective autophagosome-lysosome fusion. An impairment of the autophagic pathway was demonstrated by the inefficient degradation of exogenous aggregate-prone proteins (i.e. expanded huntingtin and mutated alpha-synuclein) in cells from LSD mice. This impairment resulted in massive accumulation of polyubiquitinated proteins and of dysfunctional mitochondria which are the putative mediators of cell death. These data identify LSDs as ‘autophagy disorders’ and suggest the presence of common mechanisms in the pathogenesis of these and other neurodegenerative diseases.
505 citations
TL;DR: The gene encoding FGE is highly conserved among pro- and eukaryotes and has a paralog of unknown function in vertebrates and is predicted to have a tripartite domain structure.
374 citations
TL;DR: Structural analysis of two catalytically active sulfatases revealed that a cysteine residue that is predicted from the cDNA sequence and conserved among all known sulfatased is replaced by a 2-amino-3-oxopropionic acid residue, while in sulfatase derived from MSD cells, this cysteined residue is retained.
359 citations
TL;DR: The identification, by functional complementation using microcell-mediated chromosome transfer, of a gene that is mutated in MSD and is able to rescue the enzymatic deficiency in patients' cell lines is reported, indicating that SUMF1 is both an essential and a limiting factor for sulfatases.
346 citations
TL;DR: The structure of N-acetylgalactosamine-4-sulfatase reveals that residues conserved amongst the sulfatase family are involved in stabilizing the calcium ion and the sulfate ester in the active site, which suggests an archetypal fold for the family of sulfatases.
297 citations