Lysosomal neuraminidase in human genetic diseases

Since the discovery of the lysosome as a distinct subcellular compartment important for intracellular digestion, by the group of De Duve in 1955, more than 70 lysosomal hydrolases have been described. A genetically determined deficiency of one of these enzymes may result in the intralysosomal accumulation of cellular constituents or extracellular products. Depending on the function of the enzyme, the rate of accumulation and the interference with the cellular metabolism, a variety of clinical and pathological manifestations will occur. Up to now more than 30 lysosomal storage disorders are known, nearly all of which are of autosomal recessive inheritance. This thesis deals with the genetic and molecular characterization of genetic diseases associated with a deficiency of lysosomal neuraminidase. Neuraminidases (EC 3.2.1.18, sialidase, N-acetyl-neuraminosyl glycohydrolase) catalyze the hydrolysis of neuraminic acid residues (sialic acids) from a variety of neuraminic acid - containing compounds. These enzymes are widely distributed in nature and in mammalian cells they form a heterogeneous group as far as their subcellular localization and substrate specificity are concerned. Our experimental work has focussed on the lysosomal neuraminidases which catalyze the cleavage of N-acetylneurarninic acid residues from glycoproteins, oligosaccharides and glycopeptides. The availability of an artificial fluorogenic substrate (4-rnethylumbelliferyl-N-acetyl-neuraminic acid) permitting a sensitive and reliable enzyme assay, has greatly facilitated both the diagnostic work and the research described in this thesis.