Role of Cathepsin D in U18666A-induced Neuronal Cell Death

Amritraj, A.; Wang, Yanlin; Revett, Timothy J.; Vergote, David; Westaway, David; Kar, Satyabrata

doi:10.1074/jbc.m112.412460

Cited by 58 publications

(24 citation statements)

References 100 publications

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“…In spleen of Npc1 nih/nih mice we also observed a striking increase in Gpnmb expression levels ( Fig 3 ). Cathepsin D expression, a marker earlier found to be elevated in Npc1 deficient mice [ 20 , 37 , 38 ], was also increased in liver and spleen of Npc1 nih/nih mice (data not shown).…”

Section: Resultsmentioning

confidence: 75%

Gpnmb Is a Potential Marker for the Visceral Pathology in Niemann-Pick Type C Disease

et al. 2016

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Impaired function of NPC1 or NPC2 lysosomal proteins leads to the intracellular accumulation of unesterified cholesterol, the primary defect underlying Niemann-Pick type C (NPC) disease. In addition, glycosphingolipids (GSLs) accumulate in lysosomes as well. Intralysosomal lipid accumulation triggers the activation of a set of genes, including potential biomarkers. Transcript levels of Gpnmb have been shown to be elevated in various tissues of an NPC mouse model. We speculated that Gpnmb could serve as a marker for visceral lipid accumulation in NPC disease. We report that Gpnmb expression is increased at protein level in macrophages in the viscera of Npc1nih/nih mice. Interestingly, soluble Gpnmb was also found to be increased in murine and NPC patient plasma. Exposure of RAW264.7 macrophages to the NPC-phenotype-inducing drug U18666A also upregulated Gpnmb expression. Inhibition of GSL synthesis with the glucosylceramide synthase (GCS) inhibitor N-butyl-1-deoxynojirimycin prevented U18666A-induced Gpnmb induction and secretion. In summary, we show that Gpnmb is upregulated in NPC mice and patients, most likely due to GSL accumulation.

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Section: Resultsmentioning

confidence: 75%

Gpnmb Is a Potential Marker for the Visceral Pathology in Niemann-Pick Type C Disease

et al. 2016

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“…Increased levels of cathD are associated with neurodegeneration like in Alzheimer’s and Gaucher’s disease or LSDs and partially appear before the onset of major pathology [51,52,53,54]. Similar effects have also been described in NPC1 for brainstem, cerebellum, hippocampus and liver [18,50,55]. …”

Section: Discussionmentioning

confidence: 92%

Increased Regenerative Capacity of the Olfactory Epithelium in Niemann–Pick Disease Type C1

Meyer

Wree

Günther

et al. 2017

IJMS

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Niemann–Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Since olfactory impairment is one of the earliest symptoms in many neurodegenerative disorders, we focused on alterations of the olfactory epithelium in an NPC1 mouse model. Previous findings revealed severe morphological and immunohistochemical alterations in the olfactory system of NPC1−/− mutant mice compared with healthy controls (NPC1+/+). Based on immunohistochemical evaluation of the olfactory epithelium, we analyzed the impact of neurodegeneration in the olfactory epithelium of NPC1−/− mice and observed considerable loss of mature olfactory receptor neurons as well as an increased number of proliferating and apoptotic cells. Additionally, after administration of two different therapy approaches using either a combination of miglustat, 2-hydroxypropyl-β-cyclodextrin (HPβCD) and allopregnanolone or a monotherapy with HPβCD, we recorded a remarkable reduction of morphological damages in NPC1−/− mice and an up to four-fold increase of proliferating cells within the olfactory epithelium. Numbers of mature olfactory receptor neurons doubled after both therapy approaches. Interestingly, we also observed therapy-induced alterations in treated NPC1+/+ controls. Thus, olfactory testing may provide useful information to monitor pharmacologic treatment approaches in human NPC1.

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“…Some of the enzymes such as cathepsins B and D are also known to affect cell viability following their release into the cytosol [28], [60]–[63]. Evidence suggests that cathepsins may be involved in the generation of Aβ peptides and their levels/expressions are increased in the vulnerable neurons as well as plasma of AD patients [33]–[35], [64]–[67].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the IGF-II/M6P Receptor in Mouse Fibroblast Cell Lines Differentially Alters Expression Profiles of Genes Involved in Alzheimer’s Disease-Related Pathology

Wang

Kar

2014

PLoS ONE

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Alzheimer’s disease (AD) is the most common type of senile dementia affecting elderly people. The processing of amyloid precursor protein (APP) leading to the generation of β-amyloid (Aβ) peptide contributes to neurodegeneration and development of AD pathology. The endocytic trafficking pathway, which comprises of the endosomes and lysosomes, acts as an important site for Aβ generation, and endocytic dysfunction has been linked to increased Aβ production and loss of neurons in AD brains. Since insulin-like growth factor-II (IGF-II) receptor plays a critical role in the transport of lysosomal enzymes from the trans-Golgi network to endosomes, it is likely that the receptor may have a role in regulating Aβ metabolism in AD pathology. However, very little is known on how altered levels of the IGF-II receptor can influence the expression/function of various molecules involved in AD pathology. To address this issue, we evaluated the expression profiles of 87 selected genes related to AD pathology in mouse fibroblast MS cells that are deficient in murine IGF-II receptor and corresponding MS9II cells overexpressing ∼500 times the human IGF-II receptors. Our results reveal that an elevation in IGF-II receptor levels alters the expression profiles of a number of genes including APP as well as enzymes regulating Aβ production, degradation and clearance mechanisms. Additionally, it influences the expression of various lysosomal enzymes and protein kinases that are involved in Aβ toxicity. IGF-II receptor overexpression also alters expression of several genes involved in intracellular signalling as well as cholesterol metabolism, which play a critical role in AD pathology. The altered gene profiles observed in this study closely match with the corresponding protein levels, with a few exceptions. These results, taken together, suggest that an elevation in IGF-II receptor levels can influence the expression profiles of transcripts as well as proteins that are involved in AD pathogenesis.

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Role of Cathepsin D in U18666A-induced Neuronal Cell Death

Cited by 58 publications

References 100 publications

Gpnmb Is a Potential Marker for the Visceral Pathology in Niemann-Pick Type C Disease

Gpnmb Is a Potential Marker for the Visceral Pathology in Niemann-Pick Type C Disease

Increased Regenerative Capacity of the Olfactory Epithelium in Niemann–Pick Disease Type C1

Overexpression of the IGF-II/M6P Receptor in Mouse Fibroblast Cell Lines Differentially Alters Expression Profiles of Genes Involved in Alzheimer’s Disease-Related Pathology

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