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

• DOI: 10.1007/s12035-017-0824-8
• Publication Date: 2017-11-22T04:46:13Z
• Authors: Blake R. Hopiavuori; Ferenc Deák; Joseph L. Wilkerson; Richard S. Brush; Nicole A. Rocha-H...; 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
• Keywords: Animal model

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