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Mol Neurobiol. 2018 Feb;55(2):1795-1813. doi: 10.1007/s12035-017-0824-8. Epub 2017 Nov 22.

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

Author information

1
Oklahoma Center for Neurosciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
2
Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
3
Oklahoma Center for Neurosciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. ferenc-deak@ouhsc.edu.
4
Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. ferenc-deak@ouhsc.edu.
5
Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. ferenc-deak@ouhsc.edu.
6
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
7
Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
8
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA.
9
Department of Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA.
10
Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
11
Department of Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA.
12
Oklahoma Center for Neurosciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. robert-anderson@ouhsc.edu.
13
Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. robert-anderson@ouhsc.edu.
14
Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. robert-anderson@ouhsc.edu.
15
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. robert-anderson@ouhsc.edu.
16
Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. robert-anderson@ouhsc.edu.
17
Oklahoma Center for Neurosciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. martin-paul-agbaga@ouhsc.edu.
18
Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. martin-paul-agbaga@ouhsc.edu.
19
Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. martin-paul-agbaga@ouhsc.edu.
20
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. martin-paul-agbaga@ouhsc.edu.
21
Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. martin-paul-agbaga@ouhsc.edu.

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.

KEYWORDS:

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

PMID:
29168048
PMCID:
PMC5820379
DOI:
10.1007/s12035-017-0824-8
[Indexed for MEDLINE]
Free PMC Article

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