Oklahoma Center for Neurosciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
Mol Neurobiol. 2018 Feb;55(2):1795-1813. doi: 10.1007/s12035-017-0824-8. Epub 2017 Nov 22.
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 mice) develop seizures by P19 and die by P21. Electrophysiological analyses of hippocampal slices showed aberrant epileptogenic activity in S Elovl4 mice. FM1-43 dye release studies showed that synapses made by cultured hippocampal neurons from S Elovl4 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.
脂质是神经系统的必需成分。然而，长链脂肪酸（VLC-FA；≥28 个碳原子）在大脑中的功能尚不清楚。酶 ELOngation of Very Long-chain fatty acids-4（ELOVL4）催化 VLC-FA（Agbaga 等人，Proc Natl Acad Sci USA 105（35）：12843-12848，2008；Logan 等人，J Lipid Res 55（4）：698-708，2014）生物合成的限速步骤，我们在大脑中鉴定出饱和脂肪酸（VLC-SFA）。ELOVL4 中的纯合突变会导致人类严重的神经病理学（Ozaki 等人，JAMA Neurol 72（7）：797-805，2015；Mir 等人，BMC Med Genet 15：25，2014；Cadieux-Dion 等人，JAMA Neurol 71（4）：470-475，2014；Bourassa 等人，JAMA Neurol 72（8）：942-943，2015；Aldahmesh 等人，Am J Hum Genet 89（6）：745-750，2011）并且在小鼠中是出生后致死的（Cameron 等人，Int J Biol Sci 3（2）：111-119，2007；Li 等人，Int J Biol Sci 3（2）：120-128，2007；McMahon 等人，Molecular Vision 13：258-272，2007；Vasireddy 等人，Hum Mol Genet 16（5）：471-482，2007）由于缺乏构成皮肤通透性屏障的 VLC-SFA 而脱水。具有 Stargardt 样黄斑营养不良（STDG3；797-801_AACTT）突变的 Elovl4 纯合敲入和皮肤特异性野生型 Elovl4 表达拯救（S_Elovl4_ 小鼠）的双转基因小鼠在 P19 时出现癫痫发作，并在 P21 时死亡。海马切片的电生理分析显示 S_Elovl4_ 小鼠中存在异常的致痫活性。FM1-43 染料释放研究表明，来自 S_Elovl4_ 小鼠的培养海马神经元形成的突触表现出加速的突触释放动力学。向突变小鼠的培养海马神经元补充 VLC-SFA 可将有缺陷的突触释放恢复到野生型速率。总之，这些研究确立了 ELOVL4 及其 VLC-SFA 产物在调节突触释放动力学和癫痫发生中的关键新作用。未来旨在了解 VLC-SFA 调节突触功能的分子机制的研究可能为改善癫痫治疗提供新的靶点。
