Effects of dietary cholesterol restriction in a feline model of Niemann–Pick type C disease

Somers, Kyra; Brown, Diane E.; Rw, Fulton; Schultheiss, Patricia C.; Hamar, Dwayne W.; Smith, M.; Allison, Robin W.; Connally, Heather E.; Just, C. A.; Mitchell, Thomas W.; Wenger, David A.; Thrall, Mary Anna

doi:10.1023/a:1010588112003

Cited by 34 publications

(15 citation statements)

References 28 publications

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“…Of note, miglustat or Genz-529468, a more effective GCS inhibitor, have been shown to significantly delay motor impairment and premature death in Npc1 -/- mice despite increased brain glucosylceramide levels [35], suggesting these inhibitors have off-target effects likely targeting the non-lysosomal glucosylceramidase. Moreover, although cholesterol-lowering approaches such as cholestyramine, statins and a low-cholesterol diet are ineffective in modifying the neurological progression of the disease [46], [47], CDX, a cholesterol-extracting agent, exhibits promising effects in ameliorating NPC pathology. CDX contains a hydrophilic exterior and a hydrophobic interior allowing it to increase the solubility of poorly water-soluble molecules such as cholesterol.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease

et al. 2017

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Niemann Pick type C (NPC) disease is a progressive lysosomal storage disorder caused by mutations in genes encoding NPC1/NPC2 proteins, characterized by neurological defects, hepatosplenomegaly and premature death. While the primary biochemical feature of NPC disease is the intracellular accumulation of cholesterol and gangliosides, predominantly in endolysosomes, mitochondrial cholesterol accumulation has also been reported. As accumulation of cholesterol in mitochondria is known to impair the transport of GSH into mitochondria, resulting in mitochondrial GSH (mGSH) depletion, we investigated the impact of mGSH recovery in NPC disease. We show that GSH ethyl ester (GSH-EE), but not N-acetylcysteine (NAC), restored the mGSH pool in liver and brain of Npc1-/- mice and in fibroblasts from NPC patients, while both GSH-EE and NAC increased total GSH levels. GSH-EE but not NAC increased the median survival and maximal life span of Npc1-/- mice. Moreover, intraperitoneal therapy with GSH-EE protected against oxidative stress and oxidant-induced cell death, restored calbindin levels in cerebellar Purkinje cells and reversed locomotor impairment in Npc1-/- mice. High-resolution respirometry analyses revealed that GSH-EE improved oxidative phosphorylation, coupled respiration and maximal electron transfer in cerebellum of Npc1-/- mice. Lipidomic analyses showed that GSH-EE treatment had not effect in the profile of most sphingolipids in liver and brain, except for some particular species in brain of Npc1-/- mice. These findings indicate that the specific replenishment of mGSH may be a potential promising therapy for NPC disease, worth exploring alone or in combination with other options.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease

et al. 2017

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“…Elevations in serum liver enzymes, bile acids, total bilirubin, and cholesterol, and decreased serum albumin have been previously reported in feline NP-C disease cats but there is are no data evaluating changes in these serum activity and concentrations over time (11). The activity of the enzymes ALT and AST were significantly greater in NP-C disease cats at all ages examined compared to wild-type cat.…”

Section: Discussionmentioning

confidence: 99%

“…The feline model has been critical for identifying the late endosomal/lysosomal accumulation of gangliosides (GM2 and GM3) and unesterified cholesterol (13), for evaluating the association of GM2 storage with meganeurite formation and abnormal dendritogenesis (10), and for correlating neuroaxonal dystrophy with neurological dysfunction (9). The feline model has also been used to evaluate the efficacy of experimental therapy of NP-C disease (11, 14). …”

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confidence: 99%

Clinical, Electrophysiological, and Serum Biochemical Measures of Progressive Neurological and Hepatic Dysfunction in Feline Niemann-Pick Type C Disease

et al. 2008

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Niemann-Pick type C (NP-C) disease is a neurovisceral lysosomal storage disease characterized by neurological dysfunction, hepatosplenomegaly, and early death. Natural history studies are very difficult to perform due to the low incidence and high heterogeneity of disease in the human population. Sixteen cats with a spontaneously occurring missense mutation in NPC1 were evaluated over time to define the progression of neurological and hepatic disease. Affected cats had remarkably regular onsets of specific signs of cerebellar and vestibular system dysfunction with progressive severity of dysfunction quantified by post-rotatory nystagmus and brain stem auditory evoked response measures. NP-C disease cats also showed increasing serum activity of alanine aminotransferase, asparate aminotransferase, and cholesterol with advancing age. Affected cats lived to a mean age of 20.5 +/- 4.8 weeks. Central nervous system and hepatic lesions were similar to those described in human patients. These data are the first to document progressive hepatic disease in the feline model and demonstrate the importance of liver disease as part of the NP-C disease phenotype. Both neurological and hepatic measures of disease onset and severity can be used as a baseline with which to assess the efficacy of experimental therapies of NP-C disease in the feline model.

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“…The feline model has been critical for identifying the late endosomal/lysosomal accumulation of gangliosides (GM2 and GM3) and unesterified cholesterol (4), for evaluating the association of ganglioside storage with meganeurite formation and ectopic dendritogenesis (16), for correlating neuroaxonal dystrophy with neurological dysfunction (2), and for evaluating efficacy of experimental therapies (16, 22, 23). The current study provides additional strong support for the efficacy of miglustat in delaying neurological signs, increasing lifespan, and improving Purkinje cell survival in NPC disease.…”

Section: Introductionmentioning

confidence: 99%

Miglustat Improves Purkinje Cell Survival and Alters Microglial Phenotype in Feline Niemann-Pick Disease Type C

Stein

Crooks

Ding

et al. 2012

J Neuropathol Exp Neurol

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Niemann-Pick disease type C (NPC disease) is an incurable cellular lipid trafficking disorder characterized by neurodegeneration and intralysosomal accumulation of cholesterol and glycosphingolipids. Treatment with miglustat, a small imino sugar that reversibly inhibits glucosylceramide synthase, which is necessary for glycosphingolipid synthesis, has been shown to benefit patients with NPC disease. The mechanism(s) and extent of brain cellular changes underlying this benefit are not understood. To investigate the basis of the efficacy of miglustat, cats with disease homologous to the juvenile-onset form of human NPC disease received daily miglustat orally beginning at 3 weeks of age. The plasma half-life of miglustat was 6.6 ± 1.1 hours, with a tmax, Cmax, and area under the plasma concentration-time curve of 1.7 ± 0.6 hours, 20.3 ± 4.6 μg/ml, and 104.1 ± 16.6 μg hours/ml, respectively. Miglustat delayed the onset of neurological signs and increased the lifespan of treated cats, and was associated with decreased GM2 ganglioside accumulation in the cerebellum and improved Purkinje cell survival. Ex vivo examination of microglia from the brains of treated cats revealed normalization of CD1c and class II major histocompatibility complex expression, as well as generation of reactive oxygen species. Together, these results suggest that prolonged Purkinje cell survival, reduced glycosphingolipid accumulation, and/or the modulation of microglial immunophenotype and function contribute to miglustat-induced neurological improvement in treated cats.

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Effects of dietary cholesterol restriction in a feline model of Niemann–Pick type C disease

Cited by 34 publications

References 28 publications

Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease

Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease

Clinical, Electrophysiological, and Serum Biochemical Measures of Progressive Neurological and Hepatic Dysfunction in Feline Niemann-Pick Type C Disease

Miglustat Improves Purkinje Cell Survival and Alters Microglial Phenotype in Feline Niemann-Pick Disease Type C

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