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Incomplete Elongation of Ultra-long-chain Polyunsaturated Acyl-CoAs by the Fatty Acid Elongase ELOVL4 in Spinocerebellar Ataxia Type 34
| Title: | Incomplete Elongation of Ultra-long-chain Polyunsaturated Acyl-CoAs by the Fatty Acid Elongase ELOVL4 in Spinocerebellar Ataxia Type 34 |
| Authors: | Tamura, Yuka Browse this author | | Sassa, Takayuki Browse this author →KAKEN DB | | Nishizawa, Takumi Browse this author | | Kihara, Akio Browse this author →KAKEN DB |
| Keywords: | ELOVL4 | | spinocerebellar ataxia | | fatty acid | | neuron | | polyunsaturated fatty acid |
| Issue Date: | 7-Feb-2023 |
| Publisher: | Taylor & Francis |
| Journal Title: | Molecular and cellular biology |
| Volume: | 43 |
| Issue: | 2 |
| Start Page: | 85 |
| End Page: | 101 |
| Publisher DOI: | 10.1080/10985549.2023.2169563 |
| Abstract: | Spinocerebellar ataxias (SCAs) are autosomal dominant diseases characterized by cerebellar atrophy and ataxia. The SCA subtype SCA34 is caused by specific mutations in the gene ELOVL4, 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 omega-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 mutated ELOVL4 may induce dominant inheritance. |
| Rights: | This is an Accepted Manuscript of an article published by Taylor & Francis in Molecular and Cellular Biology on 07 Feb. 2023, available at: http://www.tandfonline.com/10.1080/10985549.2023.2169563. |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/91300 |
| Appears in Collections: | 薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 佐々 貴之
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