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Cited by 43Sphingolipid Metabolism and SignalingAlzheimer's disease research and treatmentsLysosomal Storage Disorders Research

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

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Dominguez, Gaëlle, Maddelein, Marie-Lise, Pucelle, Mélanie, Nicaise, Yvan, Maurage, Claude-Alain, Duyckaerts, Charles, Cuvillier, Olivier, Delisle, Marie-Bernadette·2018·Acta Neuropathologica Communications
DOI 10.1186/s40478-018-0527-zPMC PMC5883421
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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.

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Authors
Dominguez, G., Maddelein, M.-L., Pucelle, M., Nicaise, Y., Maurage, C.-A., Duyckaerts, C., Cuvillier, O., & Delisle, M.-B.
Affiliations
  • Inserm (FR)
  • Centre National de la Recherche Scientifique (FR)
  • Centre Hospitalier Universitaire de Toulouse (FR)
  • Université Toulouse III - Paul Sabatier (FR)
  • Pitié-Salpêtrière Hospital (FR)
Corresponding author
Delisle, Marie-Bernadette
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2018-04-03
Volume
6
Issue
1
Pages
25-25
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-018-0527-z
PMC
PMC5883421
OpenAlex
W2802628223
Cited by
43
References
5
Citations by year
2026: 3 · 2025: 1 · 2024: 7 · 2023: 7 · 2022: 4 · 2021: 5 · 2020: 9 · 2019: 7
FWCI
1.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Association France Alzheimer (SM2015#345)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
Alzheimer's disease, sphingosine kinase 2, subcellular localization, sphingosine-1-phosphate, amyloid deposits, amyloid-beta, postmortem brain, entorhinal cortex, neuronal survival
MeSH terms
Sphingosine Kinase, Aged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Humans, Lysophospholipids, Male, Middle Aged, Sphingosine, Subcellular Fractions, Phosphotransferases (Alcohol Group Acceptor)

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