Thomas Franz Erich Willnow

ApoE4 disrupts interaction of sortilin with fatty acid-binding protein 7 essential to promote lipid signaling

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • Antonino Asaro, Max Delbrück Center for Molecular Medicine in the Helmholtz Association
  • ,
  • Rishabhdev Sinha, Max Delbrück Center for Molecular Medicine in the Helmholtz Association
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  • Magda Bakun, Institute of Biochemistry and Biophysics of the Polish Academy of Science
  • ,
  • Oleksandra Kalnytska, Max Delbrück Center for Molecular Medicine in the Helmholtz Association
  • ,
  • Anne Sophie Carlo-Spiewok, Max Delbrück Center for Molecular Medicine in the Helmholtz Association
  • ,
  • Tymon Rubel, Warsaw University of Technology
  • ,
  • Annemieke Rozeboom, University of Amsterdam
  • ,
  • Michal Dadlez, Institute of Biochemistry and Biophysics of the Polish Academy of Science, Institute of Genetics and Biotechnology, University of Warsaw, Warsaw, Poland.
  • ,
  • Bozena Kaminska, Nencki Institute of Experimental Biology of the Polish Academy of Sciences
  • ,
  • Eleonora Aronica, University of Amsterdam
  • ,
  • Anna R. Malik, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Nencki Institute of Experimental Biology of the Polish Academy of Sciences
  • ,
  • Thomas E. Willnow

Sortilin is a neuronal receptor for apolipoprotein E (apoE). Sortilin-dependent uptake of lipidated apoE promotes conversion of polyunsaturated fatty acids (PUFA) into neuromodulators that induce anti-inflammatory gene expression in the brain. This neuroprotective pathway works with the apoE3 variant but is lost with the apoE4 variant, the main risk factor for Alzheimer’s disease (AD). Here, we elucidated steps in cellular handling of lipids through sortilin, and why they are disrupted by apoE4. Combining unbiased proteome screens with analyses in mouse models, we uncover interaction of sortilin with fatty acid-binding protein 7 (FABP7), the intracellular carrier for PUFA in the brain. In the presence of apoE3, sortilin promotes functional expression of FABP7 and its ability to elicit lipid-dependent gene transcription. By contrast, apoE4 binding blocks sortilin-mediated sorting, causing catabolism of FABP7 and impairing lipid signaling. Reduced FABP7 levels in the brain of AD patients expressing apoE4 substantiate the relevance of these interactions for neuronal lipid homeostasis. Taken together, we document interaction of sortilin with mediators of extracellular and intracellular lipid transport that provides a mechanistic explanation for loss of a neuroprotective lipid metabolism in AD.

Original languageEnglish
Article numberjcs258894
JournalJournal of Cell Science
Volume134
Issue20
ISSN0021-9533
DOIs
Publication statusPublished - Oct 2021

Bibliographical note

Publisher Copyright:
© 2021. Published by The Company of Biologists Ltd

    Research areas

  • Alzheimer’s disease, Fatty acid binding protein, Polyunsaturated fatty acid, Protein sorting, VPS10P domain receptor

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