A Trial of the Treatment by Bone Marrow Transplantation in the Niemann-Pick Mice
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概要
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A new autosomal recessive gene causing sphingomyelinosis in mice is described. The disease syndrome caused by this gene has been diagnosed as an analogue of Niemann-Pick disease in humans. Affected mice cannot breed. They show neurological symptoms and weight loss beginning from around 7 weeks of age, and die at 12-14 weeks. By 8 weeks of age striking hepatosplenomegaly and marked enlargement of lymph nodes are present. Large areas of the liver and spleen are replaced by clusters of foam cells. The contents of sphingomyelin and free cholesterol in the liver and spleen are markedly elevated. But the brain shows no obvious changes in lipid concentration. Sphingomyelinase activity is reduced to about 30 percent that of the homozygous normal controls in the liver, 50 percent in the spleen and 70-80 percent in the brain. Heterozygotes are normal in both lipid concentrations and sphingomyelinase activity.<BR>The isoelectric focusing pattern of sphingomyelinase in the liver and the brain from both a control and an affected mouse was studied. In the control liver, 2 major peaks of sphingomyelinase activity were seen. One peak with a pI of 4.2, indicates acid sphingomyelinase. Other peak with a pI of 3.0 shows neutral sphingomyelinase. In the affected liver, peak with pI of 3.0 was quite similar to that of control, whereas a significant decline of peak with pI of 4.2 was noticed. On the other hand, in the control brain, the 2 major peaks of sphingomyelinase activity were also observed. However, in contrast to the liver, one peak with pI of 3.0, which indicated neutral sphingomyelinase, was the most prominent peak, and the pI of acid sphingomyelinase was different from that of the liver. In the affected brain, 2 peaks of sphingomyelinase activity were also seen. This pattern did not differ from the control brain. Subsequently, the subcellular distribution of the brain sphingomyelinases was studied. In the whole homogenate fraction, sphingomyelinase activity of the affected brain showed approximately 70% of the control activity. However, sphingomyelinase activity in the mitochondria-lysosome fraction of affected brain had only 19% of the normal control. The deficiency of lysosomal acid sphingomyelinase in the brain probably is responsible for the development of neurological manifestations in the affected mice.<BR>The Niemann-Pick mice which received bone marrow transplants showed a decreased ac-cumulation of sphingomyelin and cholesterol quantitatively and a increased activity of sphingomyelinase in their spleen and liver. The sphingomyelin deposit in the bone marrow was also reduced histochemically and foam cells in the liver and spleen were significantly decreased. However, the neurological manifestations were not improved by the bone marrow graft. Our result has encouraged us to apply bone marrow transplantation to the patients with Niemann-Pick disease except the neurological manifestation type. It also might warn of unqualified application of bone marrow transplants to humans with lysosomal storage disese showing neurologiacl involvement.
- 公益社団法人 日本実験動物学会の論文
公益社団法人 日本実験動物学会 | 論文
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