No abstract

Sandhoff disease is a progressive neurodegenerative disorder caused by mutations in the HEXB gene which encodes for the b-subunit of b-hexosaminidase A and B, resulting in ganglioside GM 2 accumulation in the brain. We now demonstrate that phospholipid metabolism is altered in both cultured neurons and in brain tissue from a mouse model of Sandhoff disease, the Hexb-/-mouse. Metabolic labelling using [methyl-14 C]choline and L-[3-3 H]serine demonstrated reduced incorporation of [methyl-14 C]choline into phospholipids in brain tissue but not in liver or spleen. Phospholipid mass was also reduced in brain. The activities of CTP : phosphocholine cytidylyltransferase (CCT) and phosphatidylserine synthase were also reduced in brain tissue from Hexb-/-mice, probably because of post-translational modification as no changes were observed in levels of enzyme expression. The relevance of these findings to Sandhoff disease in human patients is strengthened by observations made over 30 years ago on autopsy tissue of Tay Sachs and Sandhoff disease patients, in which reduced phospholipid levels were observed. We suggest that changes in phospholipid metabolism are not simply because of loss of neuronal tissue as a result of degeneration but rather may cause degeneration, and we discuss the possible effects that changes in phospholipid metabolism could play in the neuropathophysiology of Sandhoff disease. Keywords: ganglioside, lysosome, phospholipid, Sandhoff, sphingolipid, Tay Sachs. Sandhoff disease, a variant of the GM 2 gangliosidoses, belongs to a group of progressive neurodegenerative disorders characterized by significant clinical heterogeneity, ranging from acute infantile to subacute and chronic forms (Gravel et al. 2001). Patients suffering from the most severe, infantile form of the disease display neurological symptoms including weakness and hypotonia, exaggerated responses to outside stimuli, seizures and neurodeterioration from ages as early as 3-5 months, with death occurring between 2 and 4 years. In contrast to the other GM 2 gangliosidoses, such as Tay Sachs disease, Sandhoff disease patients also show visceral symptoms such as hepatosplenomegaly (Gravel et al. 2001).Sandhoff disease is caused by a defective HEXB gene which encodes for the b-subunit of b-hexosaminidase A and B and, as a result ganglioside GM 2 and the neutral glycosphingolipid, GA 2 (asialo-GM2), accumulate. The molecular basis leading from GM 2 and GA 2 accumulation to neurological disease is not known. However, the important roles that glycosphingolipids play in the physiology of neuronal tissues (Buccoliero et al. 2002;Kolter et al. 2002) suggest that their accumulation would lead to deleterious effects on neuronal function. Indeed, we have recently shown (Pelled et al. 2003b) that calcium homeostasis is altered in brain tissue and in cultured neurons from a mouse model of Sandhoff disease [the Hexb-/-mouse (Sango et al. 1995)] because of a significant reduction in the rate of calcium uptake via the sarco/endoplasmic reticulum Ca 2...

Progressive lung infiltration is a major cause of death in Niemann-Pick disease type A and B (NPA, NPB) and in the recently defined type C2. In type C1 (NPC1), the main manifestations are neurological. We report a patient with a classic, neurological, late infantile form of NPC1 disease, carrying the mutation P474L and the variant I642M in the NPC1 gene, who suffered recurrent respiratory manifestations. Bronchoalveolar lavage of a lung segment due to deteriorating respiratory condition revealed many foamy macrophages and was followed by an improvement in symptoms. Pneumopathy may therefore be considered a feature of NPC1 disease for which a partial bronchoalveolar lavage could be a useful treatment.

Sandhoff disease is caused by the defective activity of the lysosomal enzyme beta-hexosaminidase, resulting in accumulation of the glycolipids, GA2 and GM2. Niemann-Pick A/B disease is caused by the defective activity of lysosomal acid sphingomyelinase resulting in sphingomyelin accumulation. Pulmonary complications have been observed in both diseases. We now demonstrate changes in phospholipid levels in pulmonary surfactant in mouse models of these diseases. In the Hexb mouse, a model of Sandhoff disease, lipid phosphate levels were elevated in surfactant from 3- and 4-month-old mice, which was mainly due to elevated levels of phosphatidylcholine. In the ASM mouse, a model of Niemann-Pick A disease, levels of the primary storage material, sphingomyelin, were elevated as expected, and levels of phosphatidylcholine and two other phospholipids were also significantly elevated in pulmonary surfactant and in lung tissue from 5-, 6- and 7-month-old mice. These results suggest that changes in phospholipid levels and composition in lung surfactant might be a general feature of sphingolipid storage diseases, which may be in part responsible for the increased susceptibility of these patients to respiratory infections and lung pathology, often the main reason for the death of these patients.

The study of sphingolipids has undergone a renaissance over the past decade due to the realization that these lipids are involved in a variety a biological processes, such as differentiation, apoptosis, cell growth, and cell migration. In the nervous system, sphingolipids, particularly gangliosides, have attracted particular attention as they occur at high levels and their levels change in a developmentally regulated program. Despite the fact that a large body of data has accumulated on the expression and metabolism of individual gangliosides within specific brain regions, the role of individual gangliosides in neuronal development is still poorly understood, and their specific functions are only now beginning to be elucidated. In the present article, we discuss various aspects of our current knowledge concerning the involvement of sphingolipids and gangliosides in neuronal development, and then discuss some recent findings that shed light on the role of sphingolipids and gangliosides obtained with animal models of sphingolipid and other lysosomal storage diseases.