Gm1 gangliosidosis and galactosialidosis : pathogenesis and therapy

GM1 gangliosidosis and galactosialidosis belong to the large group of metabolic disorders collectively known as Iysosomal storage diseaSE!S (lSDs). lSDs are caused by a single or combined deficiency of specific hydr,olytic enzymes resulting in progressive accumulation of undigested substrates in Iysosomes of many cells, and ultimately in cellular and organ dysfunction. In general, the patients exhibit multi-systemic symptoms mostly involving severe neurological manifestations. Tlle severity and onset of the symptoms range frlom neonatal to adulthood and ofte!n correlate with the level of residual enzyme activity. Phenotypic variations are particularly Iwidenlt in the broad range of neurological symptoms that include mental retardation, motor dysfunction, sensory deficits, and seizures. Although some clinical manifestations are common in different lSDs it is becoming increasingly cleCllr that at tlhe cellular level each individual disease displays a distinct and characteristic pattern of morphological changes and extent of cellular dysfunction. The pathogenesis of each disease is, therefore, deî1ermined by the enzyme function in different cel! types and in turn by the type and amount of accumulated products. The main objective elf the present study was to gain a better understanding of the molecular bases of GMh-ganglliosidosis and galactosialidosis aml to use genetic approaches as curative therapy for murine galactosialidosos. The detailed characterization of the tWCI mouse models of these two diseases heliS provided new insights onto the molecular and cellular mechanisms that unc:lerlie neuronal degeneration in GM1 gangliosiclosis and has given the bases for implementing efficient strategies for the (;ure of galactosialidosis.