Lysosomal diseases Niemann-Pick disease

Other lysosomal storage disorders include G j gangliosidoses, G gangliosidoses, Gaucher disease, Niemann-Pick disease, Fabry disease, fucosidosis, Schindler disease, metachromatic leukodystrophy, Krabbe disease, multiple sulfatase deficiency, Farber disease, and Wolman disease. Table 28-1 illustrates the enzyme deficiencies found in some of these disorders. 

Otterbach, B., and Stoffel, W., 1995, Acid sphingomyelinase-deficient mice mimic the neurovisceral form of human lysosomal storage disease (Niemann-Pick). Cell 81 1053-1061. 

In patients with Niemann-Pick disease, inherited deficiency of this enzyme causes spingomyelin to accumulate in lysosomes of the brain, bone marrow, and other organs. 

Niemann-Pick disease. Kolodny, E.H. (2000). Curr Opin Hematol, 7 1 48-52. [647919] Intracerebral transplantation of adult mouse neural progenitor cells into the Niemann-Pick-A mouse leads to a marked decrease in lysosomal storage pathology. Shihabuddin, L.S., Numan, S., Huff, M.R., Dodge, J.C., Clarke, J., Macauley, S.L., Yang, W., Taksir, T.V., Parsons, G., Passini, M.A., Gage, F.H., Stewart, G.R. (2004). J Neurosci, 24 (47) 10642-10651. 

Lysosomal storage abnormalities, such as glycogenosis (Pompe s disease). Tay-Sachs, Krabbe s. Gaucher s, and Fabry s diseases, as well as melachromatic leukodystrophy, aspariylgiycosaminuria, and Niemann-Pick disease. Also included in this category are mucopolysaccharidoses. Hunter s, Scheie s, and Hurler s syndromes. 

Acid sphingomyelinase is a lysosomal enzyme that catalyzes the breakdown of sphingomyelin to ceramide and phosphoryl-choline.A deficiency of this enzyme leads to lysosomal accumulation of sphingomyelin in patients with Niemann-Pick disease. Recent data indicate that correct intracellular targeting of acid sphingomyelinase to lysosomes is dependent on the mannose 6-phosphate-mediated pathway. Does this imply that the I-cell patient will present with Niemann-Pick symptoms Can I-cell disease be viewed as a constellation of many lysosomal storage diseases ... 

Niemann-Pick diseases. These are also classified as lysosomal storage diseases. There are two main distinct sub-families type A (NP-A) and type B (NP-B), both caused by defects in the acid sphingomyelinase gene. Further type C diseases are caused by defects in a gene involved in LDL-cholesterol homeostasis, identified as the NPCl gene. 

These are lipids containing a fatty acid, phosphoric acid, choline and the amino alcohol, sphingosine. They are deposited in the tissues in Niemann-Pick disease, a disorder of lipid storage. In some forms of this disease, a deficiency of the lysosomal enzyme, sphingomyelinase, can be demonstrated. 

Cholesterol storage in lysosomes/endosomes is a hallmark of Niemann-Pick type C disease. The assay is based on the procedure described by Vanier et al. [58]. 

The receptors can be recycled, whereas the lipoprotein remnants in the vesicle are transferred to lysosomes and degraded by lysosomal (hydrolytic) enzymes, releasing free cholesterol, amro acids, fatty acids, and phospholipids. These compounds can be reutilized by the cell. [Note Rare autosomal recessive deficiencies in the ability to hydrolyze lysosomal cholesteryl esters (Wolman disease), or to transport unesterified cholesterol out of the lyso some (Niemann-Pick disease, type C) have been identified.]... 

In the very rare and fatal Niemann-Pick Cl disease lysosomes in cells of the central nervous system and the viscera accumulate LDL-derived cholesterol. Study of the DNA of patients led to discovery of a 1278-residue integral membrane protein, which may be required for the Golgi-mediated transport of unest-erified cholesterol from lysosomes to the ER.189/232 234c... 

The deficiency of any lysosomal enzyme results in accumulation of its substrate in lysosomes. Some of these diseases include Hurler syndrome, Hunter syndrome, I-cell disease, Niemann-Pick disease,... 

Other lines of evidence also support the notion that deregulated cholesterol homeostasis may contribute to the AD pathogenesis. AD patients have been reported to develop intracellular A/1 accumulation in the late endo-somes and lysosomes. Similar pathological features, including swollen late endosomes and A/ accumulation, have also been reported in Niemann-Pick type C disease patients [52,53], Npcl deficient mice as well as in mouse models of AD [54,55]. The Npcl gene product is essential for the mobihzation of cellular cholesterol. Excess cholesterol can be transported into endoplasmic reticulum and esterified by acyl co enzyme A cholesterol acyltransferase (ACAT) and stored in lipid droplets. Inhibition of ACAT activity has been reported to reduce A/3 levels in vitro and plaque pathology in animal models of AD [56,57]. 

Bis(monoacylglycero)phosphate (BMP) species are isomeric to PG species. In BMP, two FA chains are acylated to different glycerol molecules, whereas these FA chains are located in one glycerol in PG species. BMP plays an important role in normal lysosomal/endosomal functions in cells [62]. It has become evident that BMP is involved in the pathology of lysosomal storage diseases such as Niemann-Pick C disease (cholesterol accumulation) and certain drug-induced lipidoses [63,64]. Dys-regulation of BMP metabolism and hence of cholesterol homeostasis may also be relevant to atherosclerosis [64]. 

A group of inherited diseases in which there are deficiencies of specific lysosomal hydrolases. The diseases are characterized by the deposition of complex lipids. They include Gaucher s disease, Fabry s disease, Krabbe s disease, Tay-Sachs disease, generalized gangliosidosis, Niemann-Pick disease and metachromatic leukodystrophy. 

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