Monogenic neurological disorders of sphingolipid metabolism

Sabourdy, Frédérique; Astudillo, L.; Colacios, Céline; Dubot, Patricia; M’Rad, M. Ben; Ségui, Bruno; Levade, Thierry

doi:10.1016/j.bbalip.2015.01.010

Cited by 26 publications

(21 citation statements)

References 181 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several brain lipids have important signaling functions, including second messengers derived from sphingomyelin and phosphatidylinositol, activation of G-protein-coupled receptors, cannabinoid signaling, and nuclear receptor activation [8][9][10][11][12]. Studies in animal models show that most of the brain's sterol content is free cholesterol, 70-80% of which is in a stable myelin-associated pool, and only 0.2% of total brain cholesterol is turned over each day [13].…”

Section: Brain Lipidsmentioning

confidence: 98%

Relation between plasma and brain lipids

Wellington

Frikke‐Schmidt

2016

Current Opinion in Lipidology

View full text Add to dashboard Cite

show abstract

Section: Brain Lipidsmentioning

confidence: 98%

Relation between plasma and brain lipids

Wellington

Frikke‐Schmidt

2016

Current Opinion in Lipidology

View full text Add to dashboard Cite

show abstract

“…To date, SM translocation by ATP8A2 I364 mutants has not been examined. It would be interesting if the disease-relevant isoleucine-to-methionine substitution alters GPL versus SL preferences in the context of ATP8A2, because changes in SL distribution and metabolism have been shown to significantly impair neural function (52,53).…”

Section: Discussionmentioning

confidence: 99%

Directed evolution of a sphingomyelin flippase reveals mechanism of substrate backbone discrimination by a P4-ATPase

Roland

Graham

2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Phospholipid flippases in the type IV P-type ATPase (P4-ATPases) family establish membrane asymmetry and play critical roles in vesicular transport, cell polarity, signal transduction, and neurologic development. All characterized P4-ATPases flip glycerophospholipids across the bilayer to the cytosolic leaflet of the membrane, but how these enzymes distinguish glycerophospholipids from sphingolipids is not known. We used a directed evolution approach to examine the molecular mechanisms through which P4-ATPases discriminate substrate backbone. A mutagenesis screen in the yeast Saccharomyces cerevisiae has identified several gain-offunction mutations in the P4-ATPase Dnf1 that facilitate the transport of a novel lipid substrate, sphingomyelin. We found that a highly conserved asparagine (N220) in the first transmembrane segment is a key enforcer of glycerophospholipid selection, and specific substitutions at this site allow transport of sphingomyelin.sphingomyelin | P4-ATPase | membrane asymmetry | directed evolution T he asymmetry of the membrane bilayer is a fundamental feature of the eukaryotic plasma membrane (1). Phospholipid (PL) species such as phosphatidylserine (PS), phosphatidylinositol (PI), and phosphatidylethanolamine (PE) dominate the cytofacial leaflet, whereas phosphatidylcholine (PC) and various sphingolipids (SLs) populate the exofacial leaflet (2, 3). Organelle membrane asymmetry has proven more difficult to study, and the precise distribution of PLs is still unclear; however, evidence suggests that the organelles of the secretory and endocytic pathways also exhibit asymmetric membranes. For example, PS is initially enriched in the luminal leaflet of the endoplasmic reticulum (ER) but flips to the cytofacial leaflet at the trans-Golgi network (4). This asymmetric membrane architecture has been demonstrated to affect membrane curvature (5-8), secretory function (6, 9-16), membrane polarization (17), and intra-and intercellular signaling (17)(18)(19)(20).PL flippases in the type IV P-type ATPase family (P4-ATPases) help establish membrane asymmetry by using ATP to transport specific glycerophospholipids (GPLs) from the luminal/exofacial to the cytofacial leaflet of the membrane (21, 22). P4-ATPases have been implicated in a host of diverse diseases such as hepatic cholestasis (23-25), aberrant lymphocyte development (26, 27), anemia (27, 28), hearing loss (29), neurologic disease (30-32), and diabetes (33). Eukaryotic organisms express several P4-ATPases that have different subcellular localizations, tissue specificities, and substrate preferences (34). Understanding the substrate preferences of these enzymes and the physical means of substrate discrimination is important for understanding their role in membrane biology, development, and disease.The P-type ATPase family shares a conserved enzyme architecture that can be separated into four primary domains: the actuator (A), the nucleotide-binding (N), the phosphorylation (P), and the transmembrane (TM) domains (35). P4-ATPase substrate selection a...

show abstract

“…To date our understanding of the role of these enigmatic lipids in synapse structure and function has yet to be fully elucidated. Sphingolipids are major lipid components of the plasma and endomembrane system and have been implicated in many forms of neuropathy and neurodegeneration (for review see Sabourdy et al, ). Sphingolipids are proposed to generate structure in membranes due to their rigidity and association with cholesterol (see Munro, ).…”

Section: Introductionmentioning

confidence: 99%

Sphingolipids regulate neuromuscular synapse structure and function in Drosophila

West

Briggs

Fjeldstad

et al. 2018

J of Comparative Neurology

View full text Add to dashboard Cite

Sphingolipids are found in abundance at synapses and have been implicated in regulation of synapse structure, function, and degeneration. Their precise role in these processes, however, remains obscure. Serine Palmitoyl‐transferase (SPT) is the first enzymatic step for synthesis of sphingolipids. Analysis of the Drosophila larval neuromuscular junction (NMJ) revealed mutations in the SPT enzyme subunit, lace/SPTLC2 resulted in deficits in synaptic structure and function. Although NMJ length is normal in lace mutants, the number of boutons per NMJ is reduced to ∼50% of the wild type number. Synaptic boutons in lace mutants are much larger but show little perturbation to the general ultrastructure. Electrophysiological analysis of lace mutant synapses revealed strong synaptic transmission coupled with predominance of depression over facilitation. The structural and functional phenotypes of lace mirrored aspects of Basigin (Bsg), a small Ig‐domain adhesion molecule also known to regulate synaptic structure and function. Mutant combinations of lace and Bsg generated large synaptic boutons, while lace mutants showed abnormal accumulation of Bsg at synapses, suggesting that Bsg requires sphingolipid to regulate structure of the synapse. In support of this, we found Bsg to be enriched in lipid rafts. Our data points to a role for sphingolipids in the regulation and fine‐tuning of synaptic structure and function while sphingolipid regulation of synaptic structure may be mediated via the activity of Bsg.

show abstract

Monogenic neurological disorders of sphingolipid metabolism

Cited by 26 publications

References 181 publications

Relation between plasma and brain lipids

Relation between plasma and brain lipids

Directed evolution of a sphingomyelin flippase reveals mechanism of substrate backbone discrimination by a P4-ATPase

Sphingolipids regulate neuromuscular synapse structure and function in Drosophila

Contact Info

Product

Resources

About