Elongation of very long chain fatty acids-4 (ELOVL4) is essential for synthesis of very long chain polyunsaturated and saturated fatty acids (VLC-PUFA and VLC-SFA, respectively) of chain length greater than 26 carbons. Mutations in the ELOVL4 gene cause several distinct neurodegenerative diseases including Stargardt-like macular dystrophy (STGD3), spinocerebellar ataxia 34 (SCA34), and a neuro-ichthyotic syndrome with severe seizures and spasticity, as well as erythrokeratitis variabilis (EKV), a skin disorder. However, the relationship between ELOVL4 mutations, its VLC-PUFA and VLC-SFA products, and specific neurological symptoms remains unclear. We generated a knock-in rat line (SCA34-KI) that expresses the 736T>G (p.W246G) form of ELOVL4 that causes human SCA34. Lipids were analyzed by gas chromatography and mass spectrometry. Retinal function was assessed using electroretinography. Retinal integrity was assessed by histology, optical coherence tomography, and immunolabeling. Analysis of retina and skin lipids showed that the W246G mutation selectively impaired synthesis of VLC-SFA, but not VLC-PUFA. Homozygous SCA34-KI rats showed reduced ERG a- and b-wave amplitudes by 90 days of age, particularly for scotopic responses. Anatomical analyses revealed no indication of neurodegeneration in heterozygote or homozygote SCA34-KI rats out to 6–7 months of age. These studies reveal a previously unrecognized role for VLC-SFA in regulating retinal function, particularly transmission from photoreceptors to the inner retina, in the absence of neurodegeneration. Furthermore, these findings suggest that the tissue specificity and symptoms associated with disease-causing ELOVL4 mutations likely arise from selective differences in the ability of the mutant ELOVL4 enzymes to support synthesis of VLC-PUFA and/or VLC-SFA.

ELO的ngation v ERY升翁链脂肪酸acids- 4（ELOVL4）为链长大于26个碳的非常长链多不饱和脂肪酸和饱和脂肪酸（VLC-PUFA和VLC-SFA，分别地）的合成所必需的。ELOVL4基因的突变会引起几种明显的神经退行性疾病，包括像Stargardt样的黄斑营养不良（STGD3），脊髓小脑共济失调34（SCA34）和具有严重癫痫和痉挛的神经鱼鳞病综合征，以及皮肤红斑角膜炎（EKV）紊乱。但是，ELOVL4之间的关系突变，其VLC-PUFA和VLC-SFA产品以及特定的神经系统症状仍不清楚。我们生成了一种敲除大鼠系（SCA34-KI），它表达ELOVL4的736T> G（p.W246G）形式导致人类SCA34。通过气相色谱法和质谱法分析脂质。使用视网膜电图术评估视网膜功能。通过组织学，光学相干断层扫描和免疫标记评估视网膜完整性。视网膜和皮肤脂质的分析表明，W246G突变有选择地损害了VLC-SFA的合成，但没有损害VLC-PUFA。纯合子SCA34-KI大鼠在90天龄时显示出ERG的a波和b波振幅降低，特别是对于暗视反应。解剖分析表明，在6至7个月大的杂合子或纯合子SCA34-KI大鼠中均没有神经变性的迹象。这些研究揭示了在没有神经退行性变的情况下，VLC-SFA在调节视网膜功能，特别是从感光体到视网膜内部的传递中，以前尚未被认识的作用。此外，ELOVL4突变可能源于突变ELOVL4酶支持VLC-PUFA和/或VLC-SFA合成的能力的选择性差异。