Homozygous Expression of Mutant ELOVL4 Leads to Seizures and Death in a Novel Animal Model of Very Long-Chain Fatty Acid Deficiency

Blake R. Hopiavuori, Ferenc Deák, Joseph L. Wilkerson, Richard S. Brush, Nicole A. Rocha-Hopiavuori, Austin R. Hopiavuori, Kathryn G. Ozan, Michael T. Sullivan, Jonathan D. Wren, Constantin Georgescu, Luke Szweda, Vibhudutta Awasthi, Rheal Towner, David M. Sherry, Robert E. Anderson, Martin Paul Agbaga

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Lipids are essential components of the nervous system. However, the functions of very long-chain fatty acids (VLC-FA; ≥ 28 carbons) in the brain are unknown. The enzyme ELOngation of Very Long-chain fatty acids-4 (ELOVL4) catalyzes the rate-limiting step in the biosynthesis of VLC-FA (Agbaga et al., Proc Natl Acad Sci USA 105(35): 12843–12848, 2008; Logan et al., J Lipid Res 55(4): 698–708, 2014), which we identified in the brain as saturated fatty acids (VLC-SFA). Homozygous mutations in ELOVL4 cause severe neuropathology in humans (Ozaki et al., JAMA Neurol 72(7): 797–805, 2015; Mir et al., BMC Med Genet 15: 25, 2014; Cadieux-Dion et al., JAMA Neurol 71(4): 470–475, 2014; Bourassa et al., JAMA Neurol 72(8): 942–943, 2015; Aldahmesh et al., Am J Hum Genet 89(6): 745–750, 2011) and are post-natal lethal in mice (Cameron et al., Int J Biol Sci 3(2): 111–119, 2007; Li et al., Int J Biol Sci 3(2): 120–128, 2007; McMahon et al., Molecular Vision 13: 258–272, 2007; Vasireddy et al., Hum Mol Genet 16(5): 471–482, 2007) from dehydration due to loss of VLC-SFA that comprise the skin permeability barrier. Double transgenic mice with homozygous knock-in of the Stargardt-like macular dystrophy (STDG3; 797-801_AACTT) mutation of Elovl4 with skin-specific rescue of wild-type Elovl4 expression (S+Elovl4mut/mut mice) develop seizures by P19 and die by P21. Electrophysiological analyses of hippocampal slices showed aberrant epileptogenic activity in S+Elovl4mut/mut mice. FM1-43 dye release studies showed that synapses made by cultured hippocampal neurons from S+Elovl4mut/mut mice exhibited accelerated synaptic release kinetics. Supplementation of VLC-SFA to cultured hippocampal neurons from mutant mice rescued defective synaptic release to wild-type rates. Together, these studies establish a critical, novel role for ELOVL4 and its VLC-SFA products in regulating synaptic release kinetics and epileptogenesis. Future studies aimed at understanding the molecular mechanisms by which VLC-SFA regulate synaptic function may provide new targets for improved seizure therapies.

Original languageEnglish (US)
Pages (from-to)1795-1813
Number of pages19
JournalMolecular Neurobiology
Issue number2
StatePublished - Feb 1 2018
Externally publishedYes


  • Brain lipids
  • ELOVL4
  • Seizure
  • Synaptic dysregulation
  • Synaptic vesicle fusion kinetics
  • Very long-chain saturated fatty acids

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience


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