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

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Abstract
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 + Elovl4 mut/mut mice) develop seizures by P19 and die by P21. Electrophysiological analyses of hippocampal slices showed aberrant epileptogenic activity in S + Elovl4 mut/mut mice. FM1-43 dye release studies showed that synapses made by cultured hippocampal neurons from S + Elovl4 mut/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.
Funding Information
  • National Eye Institute (R01EY00871, R01EY04149, P30EY021725)
  • National Institute of Neurological Disorders and Stroke (R21NS090117, F31NS089358)
  • Reynolds Oklahoma Center on Aging (Collaborative Grant, Pre-doctoral Fellowship)
  • Research to Prevent Blindness (Departmental)
  • Presbyterian Health Foundation
  • Knights Templar Eye Foundation
  • BrightFocus Foundation

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