The brain lipidome in neurodegenerative lysosomal storage disorders

Fuller, Maria; Futerman, Anthony H.

doi:10.1016/j.bbrc.2018.03.042

Cited by 25 publications

(15 citation statements)

References 41 publications

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“…Within LSDs, we count several sphingolipidoses because of genetic anomalies related to either the sphingolipid hydrolytic enzyme or the activator protein necessary for the enzyme activity. Glycohydrolases are exo‐enzymes, and the incorrect catabolic process leads to the cellular primary accumulation of the enzyme substrate followed by a secondary accumulation of compounds likely as a result of lysosomal impairment (Fuller and Futerman ). In fact, secondary cell sphingolipid accumulation occurs probably in any cell with badly working lysosomes (see Table ).…”

Section: Sphingolipids and Lysosomal Storage Disorders (Lsds)mentioning

confidence: 99%

Sphingolipids and neuronal degeneration in lysosomal storage disorders

Grassi

Chiricozzi

Mauri

et al. 2018

Journal of Neurochemistry

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Ceramide, sphingomyelin, and glycosphingolipids (both neutral and acidic) are characterized by the presence in the lipid moiety of an aliphatic base known as sphingosine. Altogether, they are called sphingolipids and are particularly abundant in neuronal plasma membranes, where, via interactions with the other membrane lipids and membrane proteins, they play a specific role in modulating the cell signaling processes. The metabolic pathways determining the plasma membrane sphingolipid composition are thus the key point for functional changes of the cell properties. Unnatural changes of the neuronal properties are observed in sphingolipidoses, lysosomal storage diseases occurring when a lysosomal sphingolipid hydrolase is not working, leading to the accumulation of the substrate and to its distribution to all the cell membranes interacting with lysosomes. Moreover, secondary accumulation of sphingolipids is a common trait of other lysosomal storage diseases. Keywords: gangliosides, lysosome, membrane fusion, sphingolipidoses, sphingolipids, sphingomyelin.This article is part of the Special Issue "Lysosomal Storage Disorders".Sphingolipids are amphiphilic membrane lipids characterized by the presence of sphingosine, an amino-and-hydroxy alkylic long chain. After more than a century of studies, we now know their structure, their physico-chemical properties, their distribution and content in cells and tissues of many animal species, including humans . The final cellular site for sphingolipids is the plasma membrane, however, their complex metabolic pathway requires many intracellular processes, so that a not negligible portion of them is also found intracellularly (Sandhoff and Kolter 2003;Schulze et al. 2009;Kolter and Sandhoff 2010;Hannun and Obeid 2018). As amphiphilic compounds they contain a hydrophilic head group, for example a saccharide, an oligosaccharide, a phosphocholine, protruding into the cell aqueous environment, and a hydrophobic chain called ceramide, in which the sphingosine is linked with a fatty acid via an amidic bond, inserted into the outer layer of plasma membrane.Sphingolipids are typically asymmetric components of the plasma membranes enriched in the outer leaflet (van Meer and Hoetzl 2010;van Meer 2011;Fujimoto and Parmryd 2016), however, it cannot be excluded that a minor pool of them could be transiently inserted into the inner layer with the hydrophilic group facing the cytosol. The hydrophilic group, thanks to the presence of carbohydrates and/or ionic charges, attracts water and ions, forms hydrogen bonds and easily interacts with the group of membrane components protruding from the membrane itself. At the water-lipid interface, the sphingolipid ceramide amide linkage accepts hydrogen bonds on the carbonyl group and donates hydrogen bonds via the N-H group, allowing the formation of a double linkage, which works as a padlock within molecules (Fig. 1). The lipid moiety inserted into the lipid layer interacts with the lipid portion of the cholesterol in the membrane and with dip...

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Section: Sphingolipids and Lysosomal Storage Disorders (Lsds)mentioning

confidence: 99%

Sphingolipids and neuronal degeneration in lysosomal storage disorders

Grassi

Chiricozzi

Mauri

et al. 2018

Journal of Neurochemistry

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“…The sphingolipid signalling pathway is important for the regulation of multiple physiological processes in the brain , including neurotransmission , and for the pathologies associated with neuronal disorders . Therefore, molecules designed to mimic these compounds could interfere with the normal and pathological neuronal pathways and be useful as potential pharmacological tools.…”

Section: Fty‐720 An Analogue Of Sphingosine Revealed Multiple Possibmentioning

confidence: 99%

Emerging evidence for the modulation of exocytosis by signalling lipids

et al. 2018

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Membrane fusion is a key event in exocytosis of neurotransmitters and hormones stored in intracellular vesicles. In this process, soluble N‐ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins are essential components of the exocytotic molecular machinery, while lipids have been seen traditionally as structural elements. However, the so‐called signalling lipids, such as sphingosine and arachidonic acid, interact with SNAREs and directly modulate the frequency and mode of fusion events. Interestingly, recent work has proved that the sphingosine analogue FTY‐720, used in the treatment of multiple sclerosis, mimics the effects of signalling lipids. In the present Review, we discuss recent investigations suggesting that endogenous signalling lipids and synthetic analogues can modulate important physiological aspects of secretion, such as quantal release, vesicle recruitment into active sites, vesicle transport and even organelle fusion in the cytosol. Therefore, these compounds are far from being merely structural components of cellular membranes.

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“…Initially considered as opposite ends of the spectrum, an accumulating body of evidence shows significant similarities between cellular processes involved in both of them. 2,3,17 For that matter, an important question includes the extent to which rare neurodevelopmental diseases have progressive pathology across the lifespan into adulthood, and how these potentially neurodegenerative mechanisms may inform more common diseases. For trisomy 21 and Rett syndrome, the existence of both neurodevelopmental and neurodegenerative pathology is well-known.…”

Section: Introductionmentioning

confidence: 99%

“…However, this stability evolves towards clinical impairment and then to a degenerative course. 17,21 This is the case of some lysosomal disorders such as Sanfilippo disease, that may start with symptoms mimicking ADHD, and BPAN (an autopaghy disorder) that often presents initially as autism and Rett-like phenotype. 22 The time span between stability and progressive symptoms is variable and represents a major trait that characterizes every disease.…”

Section: Introductionmentioning

confidence: 99%

An overview of inborn errors of metabolism affecting the brain: from neurodevelopment to neurodegenerative disorders

Saudubray

García-Cazorla

2018

Dialogues in Clinical Neuroscience

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Inborn errors of metabolism (IEMs) are particularly frequent as diseases of the nervous system. In the pediatric neurologic presentations of IEMs neurodevelopment is constantly disturbed and in fact, as far as biochemistry is involved, any kind of monogenic disease can become an IEM. Clinical features are very diverse and may present as a neurodevelopmental disorder (antenatal or late-onset), as well as an intermittent, a fixed chronic, or a progressive and late-onset neurodegenerative disorder. This also occurs within the same disorder in which a continuum spectrum of severity is frequently observed. In general, the small molecule defects have screening metabolic markers and many are treatable. By contrast only a few complex molecules defects have metabolic markers and most of them are not treatable so far. Recent molecular techniques have considerably contributed in the description of many new diseases and unexpected phenotypes. This paper provides a comprehensive list of IEMs that affect neurodevelopment and may also present with neurodegeneration.

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The brain lipidome in neurodegenerative lysosomal storage disorders

Cited by 25 publications

References 41 publications

Sphingolipids and neuronal degeneration in lysosomal storage disorders

Sphingolipids and neuronal degeneration in lysosomal storage disorders

Emerging evidence for the modulation of exocytosis by signalling lipids

An overview of inborn errors of metabolism affecting the brain: from neurodevelopment to neurodegenerative disorders

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