Increased VLCFA-lipids and ELOVL4 underlie neurodegeneration in frontotemporal dementia

Ying He,Surabhi Bhatia,Olivier Piguet,Woojin Scott Kim,Katherine Phan,John R Hodges,Glenda M Halliday,Russell Pickford,Yuhong Fu,Yue Yang

doi:10.1038/s41598-021-00870-x

Ying He, Surabhi Bhatia + Show 8 more

Open Access

https://doi.org/10.1038/s41598-021-00870-x

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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.

Highlights

Rare, yet biologically critical, lipids that contain very long chain fatty acids (VLCFA-lipids) are synthesized in the brain by the enzyme ELOVL4
There was a strong correlation between the species, including the three species that were increased in frontotemporal dementia (FTD), and several examples are shown for illustration purpose (Fig. 1b)
These results strongly suggest that an increase in VLCFA-lipids in the brain is associated with the neurodegeneration observed in FTD

Summary

Introduction

Rare, yet biologically critical, lipids that contain very long chain fatty acids (VLCFA-lipids) are synthesized in the brain by the enzyme ELOVL4. VLCFA-lipids contain > 26 carbon atoms in the fatty acid chain They are normally extremely low in abundance (< 1% of total lipids)[2,3] and are synthesized by an enzyme called ELOngation of Very Long chain fatty acids 4 (ELOVL4)[4]. Both VLCFA-lipids and ELOVL4 are present in only brain, retina, skin, testes and meibomian gland[2,3,4]. We utilized quantitative discovery lipidomics to identify VLCFA-lipids that are altered in FTD brain and investigate the impact of VLCFA-lipids on membrane function

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Conclusion