Studies on neuronal death in the mouse model of Niemann‐Pick C disease

Erickson, Robert P.; Bernard, Ora

doi:10.1002/jnr.10257

Cited by 47 publications

(34 citation statements)

References 49 publications

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“…In keeping with these results, we observed cleaved caspase-3 and Fluoro-Jade C-positive Purkinje cells in the cerebellum but not in the hippocampus of Npc1 Ϫ/Ϫ mice. However, antiapoptotic strategies, such as overexpression of Bcl-2 or treatment with minocycline, that are known to prevent apoptosis in some models of neurodegenerative diseases failed to protect neurons in Npc1 Ϫ/Ϫ mice, 64 suggesting the possible existence of redundant apoptotic mechanisms in NPC pathology. Interestingly, our results revealed that the numbers of secondary lysosomes as well as of the autophagy markers LC3-II and beclin-1 are higher in both the cerebellum and hippocampus of Npc1 Ϫ/Ϫ mice compared with controls as reported in earlier studies.…”

Section: Discussionmentioning

confidence: 99%

Increased Activity and Altered Subcellular Distribution of Lysosomal Enzymes Determine Neuronal Vulnerability in Niemann-Pick Type C1-Deficient Mice

Amritraj

Peake

Kodam

et al. 2009

The American Journal of Pathology

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Niemann-Pick disease type C (NPC), caused by mutations in the Npc1 or Npc2 genes, is a progressive neurodegenerative disorder characterized by intracellular accumulation/redistribution of cholesterol in a number of tissues including the brain. This is accompanied by a severe loss of neurons in selected brain regions. In this study, we evaluated the role of lysosomal enzymes, cathepsins B and D, in determining neuronal vulnerability in NPC1-deficient (Npc1 ؊/؊ ) mouse brains. Our results showed that Npc1 ؊/؊ mice exhibit an age-dependent degeneration of neurons in the cerebellum but not in the hippocampus. The cellular level/expression and activity of cathepsins B and D are increased more predominantly in the cerebellum than in the hippocampus of Npc1 ؊/؊ mice. In addition, the cytosolic levels of cathepsins, cytochrome c, and Bax2 are higher in the cerebellum than in the hippocampus of Npc1 ؊/؊ mice, suggesting a role for these enzymes in the degeneration of neurons. This suggestion is supported by our observation that degeneration of cultured cortical neurons treated with U18666A, which induces an NPC1-like phenotype at the cellular level, can be attenuated by inhibition of cathepsin B or D enzyme activity. These results suggest that the increased level/activity and altered subcellular distribution of cathepsins may be associated with the underlying cause of neuronal vulnerability in Npc1 ؊/؊ brains. Therefore , their inhibitors may have therapeutic potential in attenuating NPC

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Section: Discussionmentioning

confidence: 99%

Increased Activity and Altered Subcellular Distribution of Lysosomal Enzymes Determine Neuronal Vulnerability in Niemann-Pick Type C1-Deficient Mice

Amritraj

Peake

Kodam

et al. 2009

The American Journal of Pathology

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“…In A-D, shown are the representative results, which were reproduced at least twice. Scale bars, 50 m. (Erickson and Bernard, 2002). A potential benefit of such a therapy against the human disease, however, remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Endosomal Accumulation of Toll-Like Receptor 4 Causes Constitutive Secretion of Cytokines and Activation of Signal Transducers and Activators of Transcription in Niemann–Pick Disease Type C (NPC) Fibroblasts: A Potential Basis for Glial Cell Activation in the NPC Brain

Suzuki¹,

Sugimoto²,

Ohsaki³

et al. 2007

J. Neurosci.

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Niemann-Pick disease type C (NPC) is an inherited lipid storage disorder caused by mutations in NPC1 or NPC2 genes. Loss of function of either protein results in the endosomal accumulation of cholesterol and other lipids, progressive neurodegeneration, and robust glial cell activation. Here, we report that cultured human NPC fibroblasts secrete interferon-␤, interleukin-6 (IL-6), and IL-8, and contain increased levels of signal transducers and activators of transcription (STATs). These cells also contained increased levels of Toll-like receptor 4 (TLR4) that accumulated in cholesterol-enriched endosomes/lysosomes, and small interfering RNA knockdown of this receptor reduced cytokine secretion. In the NPC1 Ϫ/Ϫ mouse brain, glial cells expressed TLR4 and IL-6, whereas both glial and neuronal cells expressed STATs. Genetic deletion of TLR4 in NPC1 Ϫ/Ϫ mice reduced IL-6 secretion by cultured fibroblasts but failed to alter STAT levels or glial cell activation in the brain. In contrast, genetic deletion of IL-6 normalized STAT levels and suppressed glial cell activation. These findings indicate that constitutive cytokine secretion leads to activation of STATs in NPC fibroblasts and that this secretion is partly caused by an endosomal accumulation of TLR4. These results also suggest that similar signaling events may underlie glial cell activation in the NPC1 Ϫ/Ϫ mouse brain.

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“…The comparisons made in the present study did not involve this region of brain. Other transgenic or knock-out mice in the C57BL/6 background have also been crossbred with the npc Ϫ/Ϫ BALB/c mice, without any noticeable effect on NPC pathology (Erickson and Bernard, 2002). All protocols and housing were approved by the Animal Care and Use Committee at the University of Washington.…”

Section: Methodsmentioning

confidence: 99%

p35/p25 Is Not Essential for Tau and Cytoskeletal Pathology or Neuronal Loss in Niemann–Pick Type C Disease

et al. 2006

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Hyperactivation of the cyclin-dependent kinase 5 (cdk5), triggered by proteolytic conversion of its neuronal activator, p35, to a more potent byproduct, p25, has been implicated in Alzheimer's disease (AD), amyotrophic lateral sclerosis, and Niemann-Pick type C disease (NPC). This mechanism is thought to lead to the development of neuropathological hallmarks, i.e., hyperphosphorylated cytoskeletal proteins, neuronal inclusions, and neurodegeneration, that are common to all three diseases. This pathological ensemble is recapitulated in a single model, the npc-1 (npc Ϫ/Ϫ ) mutant mouse. Previously, we showed that pharmacological cdk inhibitors dramatically reduced hyperphosphorylation, lesion formation, and locomotor defects in npc Ϫ/Ϫ mice, suggesting that cdk activity is required for NPC pathogenesis. Here, we used genetic ablation of the p35 gene to examine the specific involvement of p35, p25, and hence cdk5 activation in NPC neuropathogenesis. We found that lack of p35/p25 does not slow the onset or progression or improve the neuropathology of NPC. Our results provide direct evidence that p35/p25-mediated cdk5 deregulation is not essential for NPC pathology and suggest that similar pathology in AD may also be cdk5 independent.

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Studies on neuronal death in the mouse model of Niemann‐Pick C disease

Cited by 47 publications

References 49 publications

Increased Activity and Altered Subcellular Distribution of Lysosomal Enzymes Determine Neuronal Vulnerability in Niemann-Pick Type C1-Deficient Mice

Increased Activity and Altered Subcellular Distribution of Lysosomal Enzymes Determine Neuronal Vulnerability in Niemann-Pick Type C1-Deficient Mice

Endosomal Accumulation of Toll-Like Receptor 4 Causes Constitutive Secretion of Cytokines and Activation of Signal Transducers and Activators of Transcription in Niemann–Pick Disease Type C (NPC) Fibroblasts: A Potential Basis for Glial Cell Activation in the NPC Brain

p35/p25 Is Not Essential for Tau and Cytoskeletal Pathology or Neuronal Loss in Niemann–Pick Type C Disease

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