Unraveling the link between Neuropathy Target Esterase NTE/SWS, lysosomal storage diseases, inflammation, abnormal fatty acid metabolism, and leaky brain barrier

Abstract

Mutations in Drosophila Swiss Cheese (SWS) gene or its vertebrate orthologue Neuropathy Target Esterase (NTE) lead to progressive neuronal degeneration in flies and humans. Despite its enzymatic function as a phospholipase is well-established, the molecular mechanism responsible for maintaining nervous system integrity remains unclear. In this study, we found that NTE/SWS is present in surface glia that forms the blood-brain-barrier (BBB) and that NTE/SWS is important to maintain its structure and permeability. Importantly, BBB glia-specific expression of Drosophila NTE/SWS or human NTE in the sws mutant background fully rescues surface glial organization and partially restores BBB integrity, suggesting a conserved function of NTE/SWS. Interestingly, sws mutant glia showed abnormal organization of plasma membrane domains and tight junction rafts accompanied by the accumulation of lipid droplets, lysosomes, and multilamellar bodies. Since the observed cellular phenotypes closely resemble the characteristics described in a group of metabolic disorders known as lysosomal storage diseases (LSDs), our data established a novel connection between NTE/SWS and these conditions. We found that mutants with defective BBB exhibit elevated levels of fatty acids, which are precursors of eicosanoids and are involved in the inflammatory response. Also, as a consequence of a permeable BBB, several innate immunity factors are upregulated in an age-dependent manner, while BBB glia-specific expression of NTE/SWS normalizes inflammatory response. Treatment with anti-inflammatory agents prevents the abnormal architecture of the BBB, suggesting that inflammation contributes to the maintenance of a healthy brain barrier. Considering the link between a malfunctioning BBB and various neurodegenerative diseases, gaining a deeper understanding of the molecular mechanisms causing inflammation due to a defective BBB could help to promote the use of anti-inflammatory therapies for age-related neurodegeneration.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

  1. Mariana I Tsap

    Institute of Cell Biochemistry, Hannover Medical School, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0009-0006-0891-8504
  2. Andriy S Yatsenko

    Institute of Cell Biochemistry, Hannover Medical School, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Jan Hegermann

    Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Bibiana Beckmann

    Institute of Toxicology, Hannover Medical School, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Dimitros Tsikas

    Institute of Toxicology, Hannover Medical School, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6320-0956
  6. Halyna R Shcherbata

    Institute of Cell Biochemistry, Hannover Medical School, Hannover, Germany
    For correspondence
    Shcherbata.Halyna@mh-hannover.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3855-0345

Funding

Volkswagen Foundation (97750)

  • Halyna R Shcherbata

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2024, Tsap et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Mariana I Tsap
  2. Andriy S Yatsenko
  3. Jan Hegermann
  4. Bibiana Beckmann
  5. Dimitros Tsikas
  6. Halyna R Shcherbata
(2024)
Unraveling the link between Neuropathy Target Esterase NTE/SWS, lysosomal storage diseases, inflammation, abnormal fatty acid metabolism, and leaky brain barrier
eLife 13:e98020.
https://doi.org/10.7554/eLife.98020

Share this article

https://doi.org/10.7554/eLife.98020

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