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Cited by 26Sphingolipid Metabolism and SignalingAlzheimer's disease research and treatmentsLysosomal Storage Disorders Research

Neurodegeneration caused by S1P-lyase deficiency involves calcium-dependent tau pathology and abnormal histone acetylation

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Alam, Shah, Piazzesi, Antonia, Abd El Fatah, Mariam, Raucamp, Maren, van Echten-Deckert, Gerhild·2020·Cells
DOI 10.3390/cells9102189PMC PMC7599816
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Abstract

We have shown that sphingosine 1-phosphate (S1P) generated by sphingosine kinase 2 (SK2) is toxic in neurons lacking S1P-lyase (SGPL1), the enzyme that catalyzes its irreversible cleavage. Interestingly, patients harboring mutations in the gene encoding this enzyme (SGPL1) often present with neurological pathologies. Studies in a mouse model with a developmental neural-specific ablation of SGPL1 (SGPL1fl/fl/Nes) confirmed the importance of S1P metabolism for the presynaptic architecture and neuronal autophagy, known to be essential for brain health. We now investigated in SGPL1-deficient murine brains two other factors involved in neurodegenerative processes, namely tau phosphorylation and histone acetylation. In hippocampal and cortical slices SGPL1 deficiency and hence S1P accumulation are accompanied by hyperphosphorylation of tau and an elevated acetylation of histone3 (H3) and histone4 (H4). Calcium chelation with BAPTA-AM rescued both tau hyperphosphorylation and histone acetylation, designating calcium as an essential mediator of these (patho)physiological functions of S1P in the brain. Studies in primary cultured neurons and astrocytes derived from SGPL1fl/fl/Nes mice revealed hyperphosphorylated tau only in SGPL1-deficient neurons and increased histone acetylation only in SGPL1-deficient astrocytes. Both could be reversed to control values with BAPTA-AM, indicating the close interdependence of S1P metabolism, calcium homeostasis, and brain health.

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  • S1P accumulation induces neurodegeneration, tau pathology, and astrogliosis.

    “S1P accumulation induces neurodegeneration, tau pathology, and astrogliosis (18, 64)”

    From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [64]

    The Introduction reports that increased S1P can induce neuronal death and that S1P accumulation following SGPL1 deficiency increases tau phosphorylation. Results §3.1 confirms increased tau phosphorylation in neurons of SGPL1-deficient mice. The paper reports altered histone acetylation in astrocytes, not astrogliosis; its Discussion describes microglial activation, which is distinct. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Alam, S., Piazzesi, A., Abd El Fatah, M., Raucamp, M., & van Echten-Deckert, G.
Affiliations
  • University of Bonn (DE)
  • LIMES Institute for Membrane Biology and Lipid Biochemistry, Kekulé-Institute, University of Bonn, 53121 Bonn, Germany
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2020-09-28
Volume
9
Issue
10
Pages
2189
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells9102189
PMC
PMC7599816
OpenAlex
W3089302042
Cited by
26
References
2
Citations by year
2026: 1 · 2025: 2 · 2024: 6 · 2023: 9 · 2022: 5 · 2021: 1 · 2020: 1
FWCI
1.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Rheinische Friedrich-Wilhelms-Universität Bonn (not available)
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
sphingosine-1-phosphate, S1P metabolism, neurodegeneration, tau hyperphosphorylation, histone acetylation, calcium homeostasis, BAPTA-AM, neuronal autophagy, astrocytes, hippocampus, cortex
MeSH terms
Acetylation, Aldehyde-Lyases, Animals, Autophagy, Calcium, Histones, Humans, Lysophospholipids, Nerve Degeneration, Neurons, Protein Processing, Post-Translational, Sphingosine, tau Proteins, Tauopathies, Mice

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