Unraveling the sterol-trafficking defect in Niemann-Pick C disease

Sturley, Stephen L.; Patterson, Marc C.; Pentchev, Peter G.

doi:10.1073/pnas.0812934106

Cited by 20 publications

(11 citation statements)

References 10 publications

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“…Cholesterol content in sperm traveling through the epididymal tract may be regulated by human epididymisspecifi c proteins (HE1-HE6), initially described in the human epididymis ( 63 ). The best studied member of this group is HE1 or Niemman-Pick C2, a secreted sterol-binding glycoprotein involved in sterol traffi cking ( 64 ). The HE1 homolog has been suggested to be one of the important regulators of cholesterol content in sperm membranes at least in some species ( 65 ).…”

Section: Other Sterol Intermediates In Male Reproductionmentioning

confidence: 99%

Sterols in spermatogenesis and sperm maturation

Keber

Rozman

Horvat

2013

Journal of Lipid Research

106

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Section: Other Sterol Intermediates In Male Reproductionmentioning

confidence: 99%

Sterols in spermatogenesis and sperm maturation

Keber

Rozman

Horvat

2013

Journal of Lipid Research

106

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“…Loss of NPC1 function results in endolysosomal accumulation of unesterifi ed cholesterol ( 7,8 ), which is the hallmark of NPC disease. In NPC1-defi cient cells, cholesterol accumulation is associated with cellular oxidative stress, as evidenced by increased production of reactive oxygen species (ROS), oxidative damage, and a gene expression profi le indicative of oxidative stress ( 9, 10 ).…”

Section: Lc-ms/ms Analysismentioning

confidence: 99%

A sensitive and specific LC-MS/MS method for rapid diagnosis of Niemann-Pick C1 disease from human plasma

Jiang

Sidhu

Porter

et al. 2011

Journal of Lipid Research

230

186

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Supplementary key words cholesterol • diagnostic tools • liquid chromatography/tandem mass spectrometry • Niemann-Pick disease • oxysterols • neurodegenerationNiemann-Pick type C (NPC) disease is a rare, primarily pediatric disorder characterized by accumulation of cholesterol and other lipids in the viscera and central nervous system. Approximately 95% of NPC cases are caused by mutations of the NPC1 gene, whereas the remaining 5% are caused by mutations in the NPC2 gene ( 1, 2 ). Affected individuals typically present in early childhood with ataxia and progressive impairment of motor and intellectual function and usually die in adolescence. There are currently no FDA-approved therapies for this progressively fatal neurodegenerative disorder. However, a recent controlled study and a series of case reports suggests effi cacy for miglustat ( 3 ), an inhibitor of glycosphingolipid biosynthesis that is now licensed for use as a disease modifying therapy in multiple countries, including the European Union, Russia, Brazil, Australia, Canada, and Taiwan.Abstract Niemann-Pick type C1 (NPC1) disease is a rare, progressively fatal neurodegenerative disease for which there are no FDA-approved therapies. A major barrier to developing new therapies for this disorder has been the lack of a sensitive and noninvasive diagnostic test. Recently, we demonstrated that two cholesterol oxidation products, specifi cally cholestane-3 ␤ ,5 ␣ ,6 ␤ -triol (3 ␤ ,5 ␣ ,6 ␤ -triol) and 7-ketocholesterol (7-KC), were markedly increased in the plasma of human NPC1 subjects, suggesting a role for these oxysterols in diagnosis of NPC1 disease and evaluation of therapeutics in clinical trials. In the present study, we describe the development of a sensitive and specifi c LC-MS/ MS method for quantifying 3 ␤ ,5 ␣ ,6 ␤ -triol and 7-KC human plasma after derivatization with N,N-dimethylglycine. We show that dimethylglycine derivatization successfully enhanced the ionization and fragmentation of 3 ␤ ,5 ␣ ,6 ␤ -triol and 7-KC for mass spectrometric detection of the oxysterol species in human plasma. The oxysterol dimethylglycinates were resolved with high sensitivity and selectivity, and enabled accurate quantifi cation of 3 ␤ ,5 ␣ ,6 ␤ -triol and 7-KC concentrations in human plasma. The LC-MS/MS assay was able to discriminate with high sensitivity and specifi city between control and NPC1 subjects, and offers for the fi rst time a noninvasive, rapid, and highly sensitive method for diagnosis of NPC1

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“…As an alternative to mouse models of NPC disease, an NPC1-defi cient feline model was established ( 78,79 ) and has provided valuable information relevant to human NPC disease. Other models that have been used to elucidate pathways defective in NPC disease are mutants of yeast ( 80 ) and Drosophila ( 81,82 ). An advantage of these nonmammalian models is that genetic manipulation is relatively straightforward.…”

mentioning

confidence: 99%