Lysosomal membrane transport : physiological and pathological events / Grazia Maria Simonetta Mancini

This thesis deals with the identification of a lysosomal transport mechanism for sialic acid. A primary genetic defect of this transport mechanism is demonstrated in patients affected by lysosomal storage of free sialic acid and excessive sialuria (sialic acid storage diseases, SASD). A new patient is described, who presents with a clinical form of the disease slightly different from that of the other two well defined phenotypes (Salla disease and the infantile sialic acid storage disease, respectively). The lysosomal sialic acid carrier works as a unique H+ -cotransport system. Unexpectedly, this carrier shows a wide substrate specificity for acidic monosaccharides, including, for example, glucuronic acid. The demonstration of a transport defect for both sialic acid and glucuronic acid in lysosomes of patients with SASD introduced the concept of multiple transport defect in lysosomal disorders. In addition, a distinct carrier for neutral hexoses has been characterized, and its normal function in patients with SASD has been demonstrated. The first successful functional reconstitution of the lysosomal acidic sugar transporter, achieved in the course of our research, represents an important step to enable its purification and detailed molecular characterization