Niemann-Pick Disease Type C: Case Report with Ultastructural Findings<sup>1</sup>

Ap, Anzil; Blinzinger, K.; Mehraein, P.; Dozić, S

doi:10.1055/s-0028-1091741

Cited by 29 publications

(11 citation statements)

References 2 publications

(3 reference statements)

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“…As the prominent ataxia would suggest, cerebellar involvement, including PC degeneration, has been well documented [47–49]. The mouse model of NPC faithfully recapitulates many of the human symptoms, and PC loss serves as an easily quantifiable measure of neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Cell-Autonomous Death of Cerebellar Purkinje Neurons with Autophagy in Niemann-Pick Type C Disease

et al. 2005

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Niemann-Pick type C is a neurodegenerative lysosomal storage disorder caused by mutations in either of two genes, npc1 and npc2. Cells lacking Npc1, which is a transmembrane protein related to the Hedgehog receptor Patched, or Npc2, which is a secreted cholesterol-binding protein, have aberrant organelle trafficking and accumulate large quantities of cholesterol and other lipids. Though the Npc proteins are produced by all cells, cerebellar Purkinje neurons are especially sensitive to loss of Npc function. Since Niemann-Pick type C disease involves circulating molecules such as sterols and steroids and a robust inflammatory response within the brain parenchyma, it is crucial to determine whether external factors affect the survival of Purkinje cells (PCs). We investigated the basis of neurodegeneration in chimeric mice that have functional npc1 in only some cells. Death of mutant npc1 cells was not prevented by neighboring wild-type cells, and wild-type PCs were not poisoned by surrounding mutant npc1 cells. PCs undergoing cell-autonomous degeneration have features consistent with autophagic cell death. Chimeric mice exhibited a remarkable delay and reduction of wasting and ataxia despite their substantial amount of mutant tissue and dying cells, revealing a robust mechanism that partially compensates for massive PC death.

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Section: Discussionmentioning

confidence: 99%

Cell-Autonomous Death of Cerebellar Purkinje Neurons with Autophagy in Niemann-Pick Type C Disease

et al. 2005

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“…The combination of multiple inclusions appears to be unique to NPC. 11,73,79,80 Such changes may be detected in biopsies of the CNS, rectum, skin, and conjunctiva. False negatives may occur because of sampling error, as is true for light microscopic studies.…”

Section: Pathologymentioning

confidence: 96%

“…49,70 Cerebellar involvement is variable; in severe cases, there may be almost complete loss of granular and Purkinje cells, with residual gliosis. 49,73 Surviving Purkinje and Golgi cells, anterior horn cells, and neurons of the myenteric plexus all show evidence of excess lipid storage. 49 Studies in the NPC mouse have demonstrated preferential loss of cerebellar neurons in a striped pattern that correlates with the presence of heat shock proteins.…”

Section: Pathologymentioning

confidence: 98%

A Riddle Wrapped in a Mystery: Understanding Niemann-Pick Disease, Type C

Patterson

2003

The Neurologist

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NPC is a model for inborn errors of metabolism whose gene product mediates molecular trafficking rather than catabolizing macromolecules, as in classic lipid storage diseases. NPC should be considered in the differential diagnosis of progressive neurodegenerative disorders at any age. The astute clinician can provide great comfort to families afflicted by NPC by making an accurate diagnosis, notwithstanding the absence of definitive treatment.

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“…Cholesterol content does not appear to be elevated in cortical neurons, even though these cells exhibit neuronal storage abnormalities (Spence andCallahan, 1989,Vanier, et al, 1991), and the rate of sterol synthesis and loss is lower in NP-C mice (Xie, et al, 2000). Human NP-C brains have cortical neurons with distended cytoplasm, ballooned neurons (Anzil, et al, 1973,Braak, et al, 1983,Norman, et al, 1967, and neurofibrillary tangles . Cholesterol and sphingomyelin are decreased in white matter due to demyelination (Braak, et al, 1983,Xie, et al, 2000.…”

Section: Niemann Pick Type C Diseasementioning

confidence: 99%

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

Mellon

Gong

Schonemann

2008

Brain Research Reviews

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The functions for neurosteroids during development and in response to nervous system injury are beginning to be identified. We focused on a mouse model in which we believed neurosteroid production would be altered, and which had a neurodegenerative phenotype. Niemann Pick Type-C (NP-C) is an autosomal recessive neurodegenerative disease caused by mutations in NPC1 (95%) or NPC2 (5%), resulting in lysosomal accumulation of unesterified cholesterol and glycolipids. The NIH mouse model of NP-C has a mutation in the NPC1 gene, and exhibits several pathological features of the most severe NP-C patients. How lysosomal storage and trafficking defects lead to neurodegeneration is unknown. We found that these mice had normal neurosteroidogenic enzyme activity during development, but lost this activity in the early neonatal period, prior to onset of neurological symptoms. Neurons that expressed P450scc, 3ß HSD, as well as those that expressed 3α HSD and 5α reductase were lost in adult NP-C brains, resulting in diminished concentrations of allopregnanolone. We treated NP-C mice with allopregnanolone and found that a single dose in the neonatal period resulted in a doubling of lifespan, substantial delay in onset of neurological symptoms, survival of cerebellar Purkinje and granule cell neurons, and reduction in cholesterol and ganglioside accumulation. The mechanism by which allopregnanolone elicited these effects is unknown. Our in vitro studies showed that Purkinje cell survival promoted by allopregnanolone was lost by treatment with bicuculline, suggesting GABA A receptors may play a role. We treated NP-C mice with a synthetic GABA A neurosteroid, ganaxolone (3α-hydroxy-3β-methyl-5α -pregnan-20-one). Ganaxolone treatment of NP-C mice produced beneficial neurological effects, but these effects were not as robust as those obtained using allopregnanolone. Thus, allopregnanolone may elicit its effects through GABA A receptors and through other mechanisms. Additional studies also suggest that allopregnanolone may elicit its effects through pregnane-X receptors (PXR). Our data suggest that mouse models of neurodegeneration may be beneficial in establishing both physiologic and pharmacologic actions of neurosteroids. These animal models further establish the wide range of functions of these compounds, which may ultimately be useful for treatment of human diseases.

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Niemann-Pick Disease Type C: Case Report with Ultastructural Findings¹

Cited by 29 publications

References 2 publications

Cell-Autonomous Death of Cerebellar Purkinje Neurons with Autophagy in Niemann-Pick Type C Disease

Cell-Autonomous Death of Cerebellar Purkinje Neurons with Autophagy in Niemann-Pick Type C Disease

A Riddle Wrapped in a Mystery: Understanding Niemann-Pick Disease, Type C

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

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Niemann-Pick Disease Type C: Case Report with Ultastructural Findings1

Cited by 29 publications

References 2 publications

Cell-Autonomous Death of Cerebellar Purkinje Neurons with Autophagy in Niemann-Pick Type C Disease

Cell-Autonomous Death of Cerebellar Purkinje Neurons with Autophagy in Niemann-Pick Type C Disease

A Riddle Wrapped in a Mystery: Understanding Niemann-Pick Disease, Type C

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

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Niemann-Pick Disease Type C: Case Report with Ultastructural Findings¹