Lysosomal neuraminidase : a unique member of the sialidase superfamily

Lysosomal neuraminidase initiates the hydrolysis of oligosaccharldes, gangliosides,\nglycolipids and glycoprotelns by removing their terminal sialic acid residues. The\nenzyme functions exclusively In a multi-enzyme complex, together with flgalactosidase\nand protective protein/cathepsin A (PPCA) and Is dependent for Its\nactivity and stability on the latter protein. Mutations In the neuraminidase gene are\nthe basis for the lysosomal storage disorder sialidosls, while mutations In the PPCA\ngene Indirectly results In the Impairment of neuraminidase and p·galactosidase\nactivity, causing the lysosomal storage disorder galactoslalldosls. The experimental\nwork that is described in this thesis involves the Isolation and characterization of the\ncDNA's encoding human and mouse lysosomal neuraminidase. Structural and\nfunctional analysis of this enzyme has focused on the Interaction with PPCA in\nrelation to Its transport to the Iysosomes and the mechanism of catalytic activation.\nThese studies, In combination with the Identification and functional analysis of a\nlarge number of novel mutations In slalidosls patients, have given new Insights Into\nthe biochemical functions and properties of neuraminidase and provided reliable\nphenotype-genotype correlations. The results presented In this thesis may form the\nbasis for understanding the structural characteristics of this unusual lysosomal\nprotein and for the future development of strategies for therapy of both slalldosis\nand galactoslalldosis patients.