Increased VLCFA-lipids and ELOVL4 underlie neurodegeneration in frontotemporal dementia
Abstract Rare, yet biologically critical, lipids that contain very long chain fatty acids (VLCFA-lipids) are synthesized in the brain by the enzyme ELOVL4. High levels of VLCFA-lipids are toxic to cells and excess VLCFA-lipids are actively removed by ABCD1 in an ATP-dependent manner. Virtually nothi...
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| Main Authors: | , , , , , , , , , |
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| Format: | article |
| Language: | EN |
| Published: |
Nature Portfolio
2021
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| Subjects: | |
| Online Access: | https://doaj.org/article/a3ec9702bb7d490a87d9e995c901b490 |
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| Summary: | Abstract Rare, yet biologically critical, lipids that contain very long chain fatty acids (VLCFA-lipids) are synthesized in the brain by the enzyme ELOVL4. High levels of VLCFA-lipids are toxic to cells and excess VLCFA-lipids are actively removed by ABCD1 in an ATP-dependent manner. Virtually nothing is known about the impact of VLCFA-lipids in neurodegenerative diseases. Here, we investigated the possible role of VLCFA-lipids in frontotemporal dementia (FTD), which is a leading cause of younger-onset dementia. Using quantitative discovery lipidomics, we identified three VLCFA-lipid species that were significantly increased in FTD brain compared to controls, with strong correlations with ELOVL4. Increases in ELOVL4 expression correlated with significant decreases in the membrane-bound synaptophysin in FTD brain. Furthermore, increases in ABCD1 expression correlated with increases in VLCFA-lipids. We uncovered a new pathomechanism that is pertinent to understanding the pathogenesis of FTD. |
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