Cholesterol Accumulation Is Associated with Lysosomal Dysfunction and Autophagic Stress in Npc1−/− Mouse Brain

Liao, Guanghong; Yao, Yueqin; Liu, Jihua; Zhang, Yu; Cheung, Siu Yin; Xie, Ang; Liang, Xiaoli; Bi, Xiaoning

doi:10.2353/ajpath.2007.070052

Cited by 193 publications

(179 citation statements)

References 73 publications

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“…neurodegeneration in cathepsin D-deficient brain (42). In addition, a npc1 gene-disrupted mouse model for Niemann-Pick Type C disease showed neurodegeneration, increased numbers of AVs, and increased levels of cathepsin D and cathepsin B in the brain, indicating that cholesterol accumulation results in altered lysosome function and neuronal cell death (43). These studies support our findings that lysosomal dysfunction results in reduced turnover of AVs leading to autophagic stress-induced neuronal death, an effect that can be attenuated by blocking AV synthesis.…”

Section: Discussionsupporting

confidence: 78%

Lysosome Dysfunction Triggers Atg7-dependent Neural Apoptosis

Walls

Ghosh

Franklin

et al. 2010

Journal of Biological Chemistry

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Macroautophagy (autophagy) is a process wherein bulk cytosolic proteins and damaged organelles are sequestered and degraded via the lysosome. Alterations in autophagy-associated proteins have been shown to cause neural tube closure defects, neurodegeneration, and tumor formation. Normal lysosome function is critical for autophagy completion and when altered may lead to an accumulation of autophagic vacuoles (AVs) and caspase activation. The tumor suppressor p53 is highly expressed in neural precursor cells (NPCs) and has an important role in the regulation of both autophagy and apoptosis. We hypothesized that altered lysosome function would lead to NPC death via an interaction between autophagy-and apoptosis-associated proteins. To test our hypothesis, we utilized FGF2-expanded NPCs and the neural stem cell line, C17.2, in combination with the lysosomotropic agent chloroquine (CQ) and the vacuolar ATPase inhibitor bafilomycin A1 (Baf A1). Both CQ and Baf A1 caused concentration-and time-dependent AV accumulation, p53 phosphorylation, increased damage regulator autophagy modulator levels, caspase-3 activation, and cell death. Short hairpin RNA knockdown of Atg7, but not Beclin1, expression significantly inhibited CQ-and Baf A1-induced cell death, indicating that Atg7 is an upstream mediator of lysosome dysfunction-induced cell death. Cell death and/or caspase-3 activation was also attenuated by protein synthesis inhibition, p53 deficiency, or Bax deficiency, indicating involvement of the intrinsic apoptotic death pathway. In contrast to lysosome dysfunction, starvation-induced AV accumulation was inhibited by either Atg7 or Beclin1 knockdown, and Atg7 knockdown had no effect on starvation-induced death. These findings indicate that Atg7-and Beclin1-induced autophagy plays a cytoprotective role during starvation but that Atg7 has a unique pro-apoptotic function in response to lysosome dysfunction.

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Section: Discussionsupporting

confidence: 78%

Lysosome Dysfunction Triggers Atg7-dependent Neural Apoptosis

Walls

Ghosh

Franklin

et al. 2010

Journal of Biological Chemistry

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“…24 The activation of basal autophagy was found to be accompanied by impaired degradation of long-lived proteins, abnormal levels of the lysosomal enzyme cathepsin D, and accumulation of undigested polyubiquitinated proteins in the endolysosomal and lysosomal fraction. 22 These findings indicate that disruption of lipid trafficking in NP-C results in a global enhancement of autophagy that is, however, not sufficient to handle the quantity of proteins targeted for degradation. Importantly, induction of autophagy in NPC1-deficient cells is associated with an increased expression of Beclin-1, whereas mTOR signaling remains unchanged.…”

Section: Reviewmentioning

confidence: 88%

“…19,20 Consequently, impairment of these proteins leads to the endosomal and lysosomal accumulation of cholesterol and secondary storage of glycophospholipids in the brain and other organs. 19 In recent years, studies have demonstrated accumulation of autophagosomes in degenerating neurons of NPC1 knockout mice, [21][22][23] primary fibroblasts derived from NP-C patients, 23 and NPC1-deficient cell culture models. 24 The activation of basal autophagy was found to be accompanied by impaired degradation of long-lived proteins, abnormal levels of the lysosomal enzyme cathepsin D, and accumulation of undigested polyubiquitinated proteins in the endolysosomal and lysosomal fraction.…”

Section: Reviewmentioning

confidence: 99%

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

et al. 2013

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Pediatric neurodegenerative diseases are a heterogeneous group of diseases that result from specific genetic and biochemical defects. In recent years, studies have revealed a wide spectrum of abnormal cellular functions that include impaired proteolysis, abnormal lipid trafficking, accumulation of lysosomal content, and mitochondrial dysfunction. Within neurons, elaborated degradation pathways such as the ubiquitin-proteasome system and the autophagy-lysosomal pathway are critical for maintaining homeostasis and normal cell function. Recent evidence suggests a pivotal role for autophagy in major adult and pediatric neurodegenerative diseases. We herein review genetic, pathological, and molecular evidence for the emerging link between autophagy dysfunction and lysosomal storage disorders such as Niemann-Pick type C, progressive myoclonic epilepsies such as Lafora disease, and leukodystrophies such as Alexander disease. We also discuss the recent discovery of genetically deranged autophagy in Vici syndrome, a multisystem disorder, and the implications for the role of autophagy in development and disease. Deciphering the exact mechanism by which autophagy contributes to disease pathology may open novel therapeutic avenues to treat neurodegeneration. To this end, an outlook on novel therapeutic approaches targeting autophagy concludes this review. P ediatric neurodegenerative diseases are a heterogeneous group of diseases that result from specific genetic and biochemical defects. Although the age of onset and the clinical course are variable, neurodegenerative disorders of childhood are characterized by progressive neurologic and cognitive dysfunction with loss of speech, vision, hearing, and motor skills, and a frequent association with seizures, feeding difficulties, and failure to thrive. The degenerative process can affect white and gray matter and spreads in a disease-specific manner. Current genetic and biochemical testing and neuroimaging can establish a diagnosis. The outcome for most diseases, however, is still poor, as therapeutic approaches are limited.Accumulation of proteins, polysaccharides, and lipids are common mechanisms shared by major adult-onset neurodegenerative diseases 1-3 and many neurodegenerative diseases of childhood. 4 These conditions are, therefore, often referred to as "storage diseases" or "proteinopathies. " Cells and postmitotic cells such as neurons, in particular, rely on effective cargo targeting, tagging, transportation, and degradation to maintain intracellular homeostasis under normal conditions and metabolic stress. Within this network, autophagy plays an indispensible role by eliminating misfolded and aggregated proteins, lipids, saccharides, and damaged organelles. Recent evidence suggests that autophagy is dysregulated in a number of pediatric neurodegenerative and metabolic diseases. AUTOPHAGY: AN OVERVIEWAutophagy describes intracellular pathways that converge into degradation of target material in lysosomes. 5 The route of cargo delivery to the lysosome distinguishes th...

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“…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. 49,50 Because autophagy can be induced during both survival and death of cells, 9,65 the significance of the enhanced autophagic pathway in Npc1 Ϫ/Ϫ mice remains to be defined.…”

Section: Discussionmentioning

confidence: 99%

“…As for the autophagy marker LC3, it is known that after induction of autophagy this protein is modified from its cytosolic LC3-I form to a rapidly migrating, lipid-conjugated LC3-II form associated with autophagosomal membranes. 48,49 Beclin-1, on the other hand, is part of the class III phosphatidyl-inositol-3 kinase complex that participates in autophagosome formation. 50 Our results showed that levels of LC3-II and, to some extent, those of beclin-1 are increased in both the cerebellum and hippocampus of Npc1 Ϫ/Ϫ mice compared with controls (Supplemental …”

Section: Altered Cholesterol Distribution and Loss Of Neurons In Npc1mentioning

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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Cholesterol Accumulation Is Associated with Lysosomal Dysfunction and Autophagic Stress in Npc1−/− Mouse Brain

Cited by 193 publications

References 73 publications

Lysosome Dysfunction Triggers Atg7-dependent Neural Apoptosis

Lysosome Dysfunction Triggers Atg7-dependent Neural Apoptosis

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

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

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