TY - JOUR
T1 - Homozygous Expression of Mutant ELOVL4 Leads to Seizures and Death in a Novel Animal Model of Very Long-Chain Fatty Acid Deficiency
AU - Hopiavuori, Blake R.
AU - deák, Ferenc
AU - Wilkerson, Joseph L.
AU - Brush, Richard S.
AU - Rocha-Hopiavuori, Nicole A.
AU - Hopiavuori, Austin R.
AU - Ozan, Kathryn G.
AU - Sullivan, Michael T.
AU - Wren, Jonathan D.
AU - Georgescu, Constantin
AU - Szweda, Luke
AU - Awasthi, Vibhudutta
AU - Towner, Rheal
AU - Sherry, David M.
AU - Anderson, Robert E.
AU - Agbaga, Martin Paul
N1 - Publisher Copyright:
© 2017, The Author(s).
PY - 2018/2/1
Y1 - 2018/2/1
N2 - 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.
AB - 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.
KW - Brain lipids
KW - ELOVL4
KW - Seizure
KW - Synaptic dysregulation
KW - Synaptic vesicle fusion kinetics
KW - Very long-chain saturated fatty acids
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UR - http://www.scopus.com/inward/citedby.url?scp=85034624937&partnerID=8YFLogxK
U2 - 10.1007/s12035-017-0824-8
DO - 10.1007/s12035-017-0824-8
M3 - Article
C2 - 29168048
AN - SCOPUS:85034624937
SN - 0893-7648
VL - 55
SP - 1795
EP - 1813
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 2
ER -