Lysosomal Lipid Storage Diseases

Schulze, Heike; Sandhoff, Konrad

doi:10.1101/cshperspect.a004804

Cited by 169 publications

(156 citation statements)

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“…NPC1, a transmembrane protein with a "sterol sensing domain" and a luminal cholesterol binding domain, and NPC2, a soluble intraluminal protein capable of extracting cholesterol from lipid layers, act together to promote the recycling of cholesterol from the late-endosomal system. 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.…”

Section: Reviewmentioning

confidence: 99%

“…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%

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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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Section: Reviewmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

et al. 2013

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“…2). These reactions take place within the plasma membrane (which can generate signaling sphingolipids) as well as in the lysosome, which is an important site of sphingolipid catabolism (Mao and Obeid 2008;Jenkins et al 2009;Schulze and Sandhoff 2011). Lysosomal ceramides and LCBs generated from breakdown of mature sphingolipids exit this organelle by poorly characterized means and return to the secretory pathway, where they can be recycled to form new sphingolipids.…”

Section: Sphingolipid Turnover and Degradationmentioning

confidence: 99%

“…Conversely, an excess of sphingolipids is also toxic, leading to ER stress and disruption of calcium homeostasis (LloydEvans et al 2008;Han et al 2010). Increased levels of ceramides or LCB-Ps cause lethality in yeast (Schorling et al 2001;Zhang et al 2001), and a number of human lysosomal storage diseases, including Tay-Sachs disease, Niemann-Pick disease, and Gaucher disease, are attributable to mutations that block sphingolipid breakdown (Schulze and Sandhoff 2011). Additionally, a heredity sensory neuropathy has recently been shown to be caused by accumulation of nondegradable sphingolipid metabolites (Gable et al 2010;Penno et al 2010).…”

Section: Mechanisms Of Sphingolipid Homeostasismentioning

confidence: 99%

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

Breslow

2013

Cold Spring Harbor Perspectives in Biology

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Sphingolipids are a diverse group of lipids that have essential cellular roles as structural components of membranes and as potent signaling molecules. In recent years, a detailed picture has emerged of the basic biochemistry of sphingolipids-from their initial synthesis in the endoplasmic reticulum (ER), to their elaboration into complex glycosphingolipids, to their turnover and degradation. However, our understanding of how sphingolipid metabolism is regulated in response to metabolic demand and physiologic cues remains incomplete. Here I discuss new insights into the mechanisms that ensure sphingolipid homeostasis, with an emphasis on the ER as a critical regulatory site in sphingolipid metabolism. In particular, Orm family proteins have recently emerged as key ER-localized mediators of sphingolipid homeostasis. A detailed understanding of how cells sense and control sphingolipid production promises to provide key insights into membrane function in health and disease.

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“…For example, they are involved in embryogenesis (4), endocytosis of microbial toxins, such as cholera toxin (5), and nanoscale organization of the plasma membrane (6). Defects in GSL metabolism and turnover cause a number of lysosomal storage diseases (7). A recent review by Lingwood (1) provides a comprehensive survey of GSL functions.…”

mentioning

confidence: 99%

Reconstitution of Glucosylceramide Flip-Flop across Endoplasmic Reticulum

Chalat

Menon

Turan

et al. 2012

Journal of Biological Chemistry

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Background: Lipid flip-flop, a key feature of many glycolipid biosynthetic pathways, requires as yet unidentified flippase proteins. Results: Glucosylceramide flips slowly across protein-free vesicles but rapidly across vesicles reconstituted with ER membrane proteins. Conclusion: Glucosylceramide flipping is facilitated by ATP-independent ER phospholipid flippases. Significance: Defining how glucosylceramide is transported across membranes is critical for understanding the glycosphingolipid biosynthetic pathway.

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Lysosomal Lipid Storage Diseases

Cited by 169 publications

References 145 publications

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

Reconstitution of Glucosylceramide Flip-Flop across Endoplasmic Reticulum

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