ApoE4 disrupts interaction of sortilin with fatty acid-binding protein 7 essential to promote lipid signaling
| Autor: | Thomas E. Willnow, Eleonora Aronica, Antonino Asaro, Magda Bakun, Michal Dadlez, Tymon Rubel, Rishabhdev Sinha, Annemieke Rozeboom, Oleksandra Kalnytska, Bozena Kaminska, Anna R. Malik, Anne-Sophie Carlo-Spiewok |
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| Přispěvatelé: | Pathology, ANS - Cellular & Molecular Mechanisms |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Apolipoprotein E
Apolipoprotein E4 Apolipoprotein E3 Biology Neuroprotection Fatty acid-binding protein Protein sorting Mice Alzheimer Disease Animals Humans Fatty acid binding protein VPS10P domain receptor Chemistry Lipid metabolism Cell Biology Lipid signaling Intracellular lipid transport FABP7 Alzheimer's disease Lipids Cell biology Adaptor Proteins Vesicular Transport Polyunsaturated fatty acid Nuclear receptor Cardiovascular and Metabolic Diseases lipids (amino acids peptides and proteins) Fatty Acid-Binding Protein 7 Alzheimer’s disease Intracellular Research Article |
| Zdroj: | Asaro, A, Sinha, R, Bakun, M, Kalnytska, O, Carlo-Spiewok, A S, Rubel, T, Rozeboom, A, Dadlez, M, Kaminska, B, Aronica, E, Malik, A R & Willnow, T E 2021, ' ApoE4 disrupts interaction of sortilin with fatty acid-binding protein 7 essential to promote lipid signaling ', Journal of Cell Science, vol. 134, no. 20, jcs258894 . https://doi.org/10.1242/jcs.258894 Journal of Cell Science article-version (VoR) Version of Record Journal of cell science, 134(20):jcs258894. Company of Biologists Ltd |
| ISSN: | 0021-9533 |
| DOI: | 10.1242/jcs.258894 |
| Popis: | 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. Summary: The neuronal receptor sortilin interacts with FABP7, the carrier for intracellular lipid transport in the brain, an interaction disturbed by apoE4, the major risk factor for sporadic Alzheimer's disease. |
| Databáze: | OpenAIRE |
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