Phospholipid synthesis is decreased in neuronal tissue in a mouse model of Sandhoff disease

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...

Elevation of lung surfactant phosphatidylcholine in mouse models of Sandhoff and of Niemann–Pick A disease

“…Statistical di¡erences for total lipid phosphate and PC between Hexb þ/þ and Hexb À/À mice are indicated (* p< 0.001) Table 1 GM 2 and GA 2 levels in Hexb lung tissue. GM 2 and GA 2 were quanti¢ed in lung tissue from 3-month-old (n ¼ 15) and 4-month-old (n ¼ 15) Hexb mice Hexb þ /þ Hexb À/À Hexb þ/þ Hexb À/À (3 months) (Bodennec et al 2002) and macrophages (Trajkovic-Bodennec et al 2004) from a model of Gaucher disease, and in brain tissue of Hexb À/À mice (Buccoliero et al 2004), changes were observed in phospholipid metabolism, suggesting a dynamic interplay between these two metabolic pathways. Irrespective of the mechanism, changes in surfactant and lung phospholipid levels are entirely consistent with the lung pathology observed in Sandho¡ and Niemann^Pick diseases and with that observed in other diseases.…”

Protease-resistant modified human β-hexosaminidase B ameliorates symptoms in GM2 gangliosidosis model

“…To the best of our knowledge, this is the first demonstration of the relationship between the therapeutic effects of a treatment and imaging data obtained by IMS. As the contributions of lyso-GM2, phospholipids, and myelin-enriched lipids to the neuropathogenesis of glycosphingolipodosis was suggested (2,(54)(55)(56), multitarget validation by IMS for disease-related and therapeutic biomarkers including brain lipids will be very helpful for elucidation of the neuropathogenic mechanism in small animal disease models and monitoring combined drug therapy in preclinical studies. We anticipate that i.c.v.ERT and/or GT utilizing the modified HEXB will be subjected to preclinical studies and clinical trials leading to clinical applications for the treatment of TSD patients in the near future not only in high-risk Ashkenazi-Jewish patients, but also in non-Jewish populations worldwide.…”

CTP:Phosphocholine Cytidylyltransferase: Paving the Way from Gene to Membrane

“…For example, Gaucher disease cells accumulate glucosylceramide, which directly activates CCT and stimulates PC synthesis (95). In Sandhoff disease, an accumulation of ganglioside GM2 is associated with reduced CCT activity and PC mass in the brain (96). In both diseases, altered PC synthesis may contribute to the pathology (97).…”