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J. Biol. Chem., Vol. 279, Issue 35, 37021-37029, August 27, 2004

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Neu4, a Novel Human Lysosomal Lumen Sialidase, Confers Normal Phenotype to Sialidosis and Galactosialidosis Cells^*

Volkan Seyrantepe, Karine Landry, Stéphanie Trudel, Jacob A. Hassan¶, Carlos R. Morales¶, and Alexey V. Pshezhetsky||

From the Department of Medical Genetics, Sainte-Justine Hospital, University of Montréal, Montréal, Quebec H3T 1C5 and the ^¶Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Montréal, Quebec H3A 2B2, Canada

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-phospate 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.

Received for publication, April 23, 2004 , and in revised form, June 10, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) NM_080741, NM_000434, NP_005374, and Q9UQ49.

^* This work was supported in part by Operating Grants FRN 15079 and MT-38107 from the Canadian Institutes of Health Research, Genome Quebec Grant G202504, and by an equipment grant from the Canadian Foundation for Innovation (to A. V. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a postdoctoral fellowship from the Fonds de la Recherche en Santé du Québec and Fondation de l'Hôpital Sainte-Justine.

^|| National Investigator of Fonds de la Recherche en Santé du Québec. To whom correspondence should be addressed: Service de Génétique Médicale, Hôpital Sainte-Justine, 3175 Côte Ste-Catherine, Montréal, Quebec H3T 1C5, Canada. Tel.: 514-345-4931 (ext. 2736); Fax: 514-345-4801; E-mail: alexei.pchejetski{at}umontreal.ca.

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