title: Neu4, a novel human lysosomal lumen sialidase, confers normal phenotype to sialidosis and galactosialidosis cells.
abstract: Three different mammalian sialidases have been described as follows: lysosomal (Neu1, gene NEU1), cytoplasmic (Neu2, gene NEU2), and plasma membrane (Neu3, gene NEU3). Because of mutations in the NEU1 gene, the inherited deficiency of Neu1 in humans causes the severe multisystemic neurodegenerative disorder sialidosis. Galactosialidosis, a clinically similar disorder, is caused by the secondary Neu1 deficiency because of genetic defects in cathepsin A that form a complex with Neu1 and activate it. In this study we describe a novel lysosomal lumen sialidase encoded by the NEU4 gene on human chromosome 2. We demonstrate that Neu4 is ubiquitously expressed in human tissues and has broad substrate specificity by being active against sialylated oligosaccharides, glycoproteins, and gangliosides. In contrast to Neu1, Neu4 is targeted to lysosomes by the mannose 6-phosphate receptor and does not require association with other proteins for enzymatic activity. Expression of Neu4 in the cells of sialidosis and galactosialidosis patients results in clearance of storage materials from lysosomes suggesting that Neu4 may be useful for developing new therapies for these conditions.
authors.affiliation: Department of Medical Genetics, Sainte-Justine Hospital, University of Montréal, 3175 Côte Ste-Catherine, Montréal, Quebec H3T 1C5, Canada.
authors.forename: Volkan
authors.initials: V
authors.lastname: Seyrantepe
authors.forename: Karine
authors.initials: K
authors.lastname: Landry
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Trudel
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Hassan
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Morales
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Pshezhetsky
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D019556:COS Cells; D002384:Catalysis; D002462:Cell Membrane / Q000378:metabolism; D002889:Chromosomes, Human, Pair 2 / Q000648:ultrastructure; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008164:Luminescent Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D013058:Mass Spectrometry; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009081:Mucolipidoses; D009154:Mutation; D009439:Neuraminidase / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012867:Skin / Q000378:metabolism; D013347:Subcellular Fractions; D013379:Substrate Specificity; D014018:Tissue Distribution; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D008164:Luminescent Proteins; D017527:Receptor, IGF Type 2; D049452:Green Fluorescent Proteins; C491428:NEU4 protein, human; C481539:Neu4 protein, mouse; D009439:Neuraminidase