La sphingosine 1-phosphate comme biomarqueur de la maladie d’Alzheimer ?

Ceccom, Johnatan; Delisle, Marie–Bernadette

doi:10.1051/medsci/20143005006

Cited by 5 publications

(4 citation statements)

References 15 publications

(22 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A deregulation of sphingolipid metabolism and more particularly S1P signaling has been recently stressed in AD (reviewed in [ 7 , 9 , 28 , 38 , 52 ]). Initial work in neuronal cell models showed that apoptosis induced by Aβ peptide was dependent on increased production of pro-apoptotic ceramide [ 30 ] or decreased activity of SphK1 leading to decreased content of pro-survival S1P [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Neuronal sphingosine kinase 2 subcellular localization is altered in Alzheimer’s disease brain

Dominguez

Maddelein

Pucelle

et al. 2018

acta neuropathol commun

Self Cite

View full text Add to dashboard Cite

BackgroundAlzheimer’s disease (AD) is characterized by the accumulation of β-amyloid (Aβ) peptides and hyperphosphorylated tau protein accompanied by neuronal loss. Aβ accumulation has been associated with an impaired sphingosine 1-phosphate (S1P) metabolism. S1P is generated by sphingosine kinases (SphKs), of which there are two isoenzymes SphK1 and SphK2, and degraded by the sphingosine 1-phosphate lyase (SPL). We previously reported, that both a decrease in SphK1 expression and an increase in SPL expression, correlated with amyloid deposits in the entorhinal cortex of AD brains, suggesting a global loss of pro-survival S1P in AD neurons. SphK2 contribution has also been examined in AD yielding to conflicting results that may reflect the complexity of SphK2 regulation. The subcellular localization of SphK2, hence the compartmentalization of generated S1P, is recognized to play a crucial role in dictating either its pro-survival or pro-apoptotic functions. We therefore aimed at studying the expression of SphK2 and notably its subcellular localization in brain tissues from patients with AD.ResultsWe report that a decrease in SphK2 protein cytosolic expression correlated with the density of amyloid deposits in a cohort of 25 post-mortem brains. Interestingly, we observed that the equilibrium between cytoplasmic and nuclear SphK2 is disrupted and showed that SphK2 is preferentially localized in the nucleus in AD brain extracts as compared to control extracts, with a marked increase of cleaved SphK2.ConclusionsOur results suggest that a shift in the subcellular localization of the S1P generating SphK2 may compromise the well established pro-survival cytosolic S1P by favoring the production of nuclear S1P associated with adverse effects in AD pathogenesis.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0527-z) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Neuronal sphingosine kinase 2 subcellular localization is altered in Alzheimer’s disease brain

Dominguez

Maddelein

Pucelle

et al. 2018

acta neuropathol commun

Self Cite

View full text Add to dashboard Cite

show abstract

“…Evidence indicates that defective sphingolipid metabolism may likely contribute to different neurodegenerative conditions, including HD (Desplats et al, 2007 ; Maglione et al, 2010 ; Ceccom et al, 2014a , b ; Couttas et al, 2014 , 2016 ; Di Pardo et al, 2016 , 2017a ). We and others have recently demonstrated that alterations in the sphingolipid metabolism occur early in the disease stage and may play, therefore, a critical role in the pathogenesis of HD (Di Pardo et al, 2016 , 2017a ; Skene et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

De novo Synthesis of Sphingolipids Is Defective in Experimental Models of Huntington's Disease

et al. 2017

View full text Add to dashboard Cite

Alterations of lipid metabolism have been frequently associated with Huntington's disease (HD) over the past years. HD is the most common neurodegenerative disorder, with a complex pathogenic profile, typically characterized by progressive striatal and cortical degeneration and associated motor, cognitive and behavioral disturbances. Previous findings from our group support the idea that disturbed sphingolipid metabolism could represent an additional hallmark of the disease. Although such a defect represents a common biological denominator among multiple disease models ranging from cells to humans through mouse models, more efforts are needed to clearly define its clinical significance and the role it may play in the progression of the disease. In this study, we provided the first evidence of a defective de novo biosynthetic pathway of sphingolipids in multiple HD pre-clinical models. qPCR analysis revealed perturbed gene expression of sphingolipid-metabolizing enzymes in both early and late stage of the disease. In particular, reduction in the levels of sptlc1 and cerS1 mRNA in the brain tissues from manifest HD mice resulted in a significant decrease in the content of dihydroSphingosine, dihydroSphingosine-1-phospahte and dihydroCeramide [C18:0] as assessed by mass spectrometry. Moreover, in vitro studies highlighted the relevant role that aberrant sphingolipid metabolism may have in the HD cellular homeostasis. With this study, we consolidate the evidence of disturbed sphingolipid metabolism in HD and demonstrate for the first time that the de novo biosynthesis pathway is also significantly affected in the disease. This finding further supports the hypothesis that perturbed sphingolipid metabolism may represent a crucial factor accounting for the high susceptibility to disease in HD.

show abstract

“…A number of evidence also indicates that, along with ceramide abnormalities, metabolism of other sphingolipids is affected in AD (Zheng et al, 2006 ; Mielke and Lyketsos, 2010 ). Also, alteration in the expression and/or in the activity of S1P-metabolizing enzymes as well as reduced levels of S1P has been widely reported in AD human brains (Katsel et al, 2007 ; Ceccom et al, 2014a , b ; Couttas et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Sphingolipid Metabolism: A New Therapeutic Opportunity for Brain Degenerative Disorders

Pardo

Maglione

2018

Front. Neurosci.

View full text Add to dashboard Cite

Neurodegenerative diseases represent a class of fatal brain disorders for which the number of effective therapeutic options remains limited with only symptomatic treatment accessible. Multiple studies show that defects in sphingolipid pathways are shared among different brain disorders including neurodegenerative diseases and may contribute to their complex pathogenesis. In this mini review, we discuss the hypothesis that modulation of sphingolipid metabolism and their related signaling pathways may represent a potential therapeutic approach for those devastating conditions. The plausible “druggability” of sphingolipid pathways is greatly promising and represent a relevant feature that brings real advantage to the development of new therapeutic options for these conditions. Indeed, several molecules that selectively target sphingolipds are already available and many of them currently in clinical trial for human diseases. A deeper understanding of the “sphingolipid scenario” in neurodegenerative disorders would certainly enhance therapeutic perspectives for these conditions, by taking advantage from the already available molecules and by promoting the development of new ones.

show abstract

La sphingosine 1-phosphate comme biomarqueur de la maladie d’Alzheimer ?

Cited by 5 publications

References 15 publications

Neuronal sphingosine kinase 2 subcellular localization is altered in Alzheimer’s disease brain

Neuronal sphingosine kinase 2 subcellular localization is altered in Alzheimer’s disease brain

De novo Synthesis of Sphingolipids Is Defective in Experimental Models of Huntington's Disease

Sphingolipid Metabolism: A New Therapeutic Opportunity for Brain Degenerative Disorders

Contact Info

Product

Resources

About