Incomplete Elongation of Ultra-long-chain Polyunsaturated Acyl-CoAs by the Fatty Acid Elongase ELOVL4 in Spinocerebellar Ataxia Type 34
Incomplete Elongation of Ultra-long-chain Polyunsaturated Acyl-CoAs by the Fatty Acid Elongase ELOVL4 in Spinocerebellar Ataxia Type 34
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DOI：
10.1080/10985549.2023.2169563
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发表时间：
2023-02-06
影响因子：
5.3
通讯作者：
Kihara，Akio
中科院分区：
文献类型：
--
作者：
Tamura，Yuka;Sassa，Takayuki;Kihara，Akio
脊髓小脑共济失调（SCAs）是常染色体显性遗传病，以小脑萎缩和共济失调为特征。SCA亚型SCA34是由基因elovl4的特异性突变引起的，该基因编码一种合成超长链（ULC;≥C26） FAs的脂肪酸（FA）延长酶。然而，显性遗传的发病机制和分子机制尚不清楚。在这里，一项基于细胞的实验表明，五个已知的SCA34突变体中的每一个都比野生型蛋白产生更短的ULC多不饱和fa -含磷脂酰胆碱（ULC- pcs），其严重程度如下：Q180P和T233M > W246G > I171T和L168F。接下来，我们产生了含有杂合子Q180P、杂合子W246G或纯合子W246G突变的敲入小鼠胚胎干细胞。与对照细胞相比，杂合子Q180P和纯合子W246G细胞的神经元分化依赖性ULC-PCs的产生减少，我们观察到所有突变细胞的FA片段都缩短了。这种FA缩短与我们的预测一致，即被SCA34突变取代的氨基酸残基位于与底物酰基辅酶a的FA部分ω端区相互作用的跨膜螺旋上。因此，神经元中ULC- pcs水平的降低和缩短可能导致SCA34，而突变的elovl4导致ULC多不饱和酰基辅酶a的不完全伸长可能导致显性遗传。
Spinocerebellar ataxias (SCAs) are autosomal dominant diseases characterized by cerebellar atrophy and ataxia. The SCA subtype SCA34 is caused by specific mutations in the geneELOVL4, which encodes a fatty acid (FA) elongase that synthesizes ultra-long-chain (ULC; ≥C26) FAs. However, the pathogenesis and molecular mechanism that confers dominant inheritance remains unknown. Here, a cell-based assay demonstrated that each of the five known SCA34 mutants produced shorter ULC polyunsaturated FA-containing phosphatidylcholines (ULC-PCs) than wild-type protein, in the following order of severity: Q180P and T233M > W246G > I171T and L168F. Next, we generated knock-in mouse embryonic stem cells that contained heterozygous Q180P, heterozygous W246G, or homozygous W246G mutations. Neuronal differentiation-dependent production of ULC-PCs was reduced in heterozygous Q180P and homozygous W246G cells relative to control cells, and we observed shortening of the FA moiety in all mutant cells. This FA shortening was consistent with our prediction that amino acid residues substituted by SCA34 mutations are located in the transmembrane helices that interact with the ω-end region of the FA moiety of the substrate acyl-CoA. Hence, reduced levels and shortening of ULC-PCs in neurons may cause SCA34, and incomplete elongation of ULC polyunsaturated acyl-CoAs by mutatedELOVL4may induce dominant inheritance.