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

Acta Neuropathologica Communications

Mélanie Pucelle¹  Marie-Lise Maddelein²  Olivier Cuvillier²  Charles Duyckaerts³  Claude-Alain Maurage⁴  Yvan Nicaise⁵  Marie-Bernadette Delisle⁶  Gaëlle Dominguez⁶ 

[1] CHU de Toulouse, Laboratoire de Neuropathologie;Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS;Laboratoire de Neuropathologie et Centre de Recherche de l’ICM, Hôpital de la Salpétrière;Université Lille, Inserm;Université de Toulouse III, Faculté de Médecine Rangueil;Université de Toulouse, Inserm UMR 1214;

关键词: Alzheimer’s disease;    Neuropathology;    β-amyloid;    Sphingolipids;    Sphingosine kinase 2;    Sphingosine 1-phosphate;   

DOI  :  10.1186/s40478-018-0527-z

来源: DOAJ

【 摘 要 】

Abstract Background Alzheimer’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. Results We 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. Conclusions Our 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.

【 授权许可】

Unknown