Rare Neurologic Disease-Associated Mutations of AIMP1 Are Related with Inhibitory Neuronal Differentiation Which Is Reversed by Ibuprofen
<b>Background:</b> Hypomyelinating leukodystrophy 3 (HLD3), previously characterized as a congenital diseases associated with oligodendrocyte myelination, is increasingly regarded as primarily affecting neuronal cells. <b>Methods:</b> We used N1E-115 cells as the neuronal cel...
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MDPI AG
2020-05-01
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| Online Access: | https://www.mdpi.com/2305-6320/7/5/25 |
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| author | Yu Takeuchi Marina Tanaka Nanako Okura Yasuyuki Fukui Ko Noguchi Yoshihiro Hayashi Tomohiro Torii Hiroaki Ooizumi Katsuya Ohbuchi Kazushige Mizoguchi Yuki Miyamoto Junji Yamauchi |
| author_facet | Yu Takeuchi Marina Tanaka Nanako Okura Yasuyuki Fukui Ko Noguchi Yoshihiro Hayashi Tomohiro Torii Hiroaki Ooizumi Katsuya Ohbuchi Kazushige Mizoguchi Yuki Miyamoto Junji Yamauchi |
| author_sort | Yu Takeuchi |
| collection | DOAJ |
| description | <b>Background:</b> Hypomyelinating leukodystrophy 3 (HLD3), previously characterized as a congenital diseases associated with oligodendrocyte myelination, is increasingly regarded as primarily affecting neuronal cells. <b>Methods:</b> We used N1E-115 cells as the neuronal cell model to investigate whether HLD3-associated mutant proteins of cytoplasmic aminoacyl-tRNA synthase complex-interacting multifunctional protein 1 (AIMP1) aggregate in organelles and affect neuronal differentiation. <b>Results:</b> 292CA frame-shift type mutant proteins harboring a two-base (CA) deletion at the 292th nucleotide are mainly localized in the lysosome where they form aggregates. Similar results are observed in mutant proteins harboring the Gln39-to-Ter (Q39X) mutation. Interestingly, the frame-shift mutant-specific peptide specifically interacts with actin to block actin fiber formation. The presence of actin with 292CA mutant proteins, but not with wild type or Q39X ones, in the lysosome is detectable by immunoprecipitation of the lysosome. Furthermore, expression of 292CA or Q39X mutants in cells inhibits neuronal differentiation. Treatment with ibuprofen reverses mutant-mediated inhibitory differentiation as well as the localization in the lysosome. <b>Conclusions:</b> These results not only explain the cell pathological mechanisms inhibiting phenotype differentiation in cells expressing HLD3-associated mutants but also identify the first chemical that restores such cells in vitro. |
| first_indexed | 2024-03-10T20:00:05Z |
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| id | doaj.art-24559466e3134eea96f1de101192aaaf |
| institution | Directory Open Access Journal |
| issn | 2305-6320 |
| language | English |
| last_indexed | 2024-03-10T20:00:05Z |
| publishDate | 2020-05-01 |
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| series | Medicines |
| spelling | doaj.art-24559466e3134eea96f1de101192aaaf2023-11-19T23:38:37ZengMDPI AGMedicines2305-63202020-05-01752510.3390/medicines7050025Rare Neurologic Disease-Associated Mutations of AIMP1 Are Related with Inhibitory Neuronal Differentiation Which Is Reversed by IbuprofenYu Takeuchi0Marina Tanaka1Nanako Okura2Yasuyuki Fukui3Ko Noguchi4Yoshihiro Hayashi5Tomohiro Torii6Hiroaki Ooizumi7Katsuya Ohbuchi8Kazushige Mizoguchi9Yuki Miyamoto10Junji Yamauchi11Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, JapanLaboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, JapanLaboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, JapanLaboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, JapanLaboratory of Applied Ecology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, JapanLaboratory of Oncology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, JapanLaboratory of Ion Channel Pathophysiology, Doshisha University, Kyotanabe, Kyoto 610-0394, JapanTsumura Research Laboratories, Tsumura & Co., Inashiki, Ibaraki 200-1192, JapanTsumura Research Laboratories, Tsumura & Co., Inashiki, Ibaraki 200-1192, JapanTsumura Research Laboratories, Tsumura & Co., Inashiki, Ibaraki 200-1192, JapanLaboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, JapanLaboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan<b>Background:</b> Hypomyelinating leukodystrophy 3 (HLD3), previously characterized as a congenital diseases associated with oligodendrocyte myelination, is increasingly regarded as primarily affecting neuronal cells. <b>Methods:</b> We used N1E-115 cells as the neuronal cell model to investigate whether HLD3-associated mutant proteins of cytoplasmic aminoacyl-tRNA synthase complex-interacting multifunctional protein 1 (AIMP1) aggregate in organelles and affect neuronal differentiation. <b>Results:</b> 292CA frame-shift type mutant proteins harboring a two-base (CA) deletion at the 292th nucleotide are mainly localized in the lysosome where they form aggregates. Similar results are observed in mutant proteins harboring the Gln39-to-Ter (Q39X) mutation. Interestingly, the frame-shift mutant-specific peptide specifically interacts with actin to block actin fiber formation. The presence of actin with 292CA mutant proteins, but not with wild type or Q39X ones, in the lysosome is detectable by immunoprecipitation of the lysosome. Furthermore, expression of 292CA or Q39X mutants in cells inhibits neuronal differentiation. Treatment with ibuprofen reverses mutant-mediated inhibitory differentiation as well as the localization in the lysosome. <b>Conclusions:</b> These results not only explain the cell pathological mechanisms inhibiting phenotype differentiation in cells expressing HLD3-associated mutants but also identify the first chemical that restores such cells in vitro.https://www.mdpi.com/2305-6320/7/5/25AIMP1mutationdifferentiationactinibuprofen |
| spellingShingle | Yu Takeuchi Marina Tanaka Nanako Okura Yasuyuki Fukui Ko Noguchi Yoshihiro Hayashi Tomohiro Torii Hiroaki Ooizumi Katsuya Ohbuchi Kazushige Mizoguchi Yuki Miyamoto Junji Yamauchi Rare Neurologic Disease-Associated Mutations of AIMP1 Are Related with Inhibitory Neuronal Differentiation Which Is Reversed by Ibuprofen Medicines AIMP1 mutation differentiation actin ibuprofen |
| title | Rare Neurologic Disease-Associated Mutations of AIMP1 Are Related with Inhibitory Neuronal Differentiation Which Is Reversed by Ibuprofen |
| title_full | Rare Neurologic Disease-Associated Mutations of AIMP1 Are Related with Inhibitory Neuronal Differentiation Which Is Reversed by Ibuprofen |
| title_fullStr | Rare Neurologic Disease-Associated Mutations of AIMP1 Are Related with Inhibitory Neuronal Differentiation Which Is Reversed by Ibuprofen |
| title_full_unstemmed | Rare Neurologic Disease-Associated Mutations of AIMP1 Are Related with Inhibitory Neuronal Differentiation Which Is Reversed by Ibuprofen |
| title_short | Rare Neurologic Disease-Associated Mutations of AIMP1 Are Related with Inhibitory Neuronal Differentiation Which Is Reversed by Ibuprofen |
| title_sort | rare neurologic disease associated mutations of aimp1 are related with inhibitory neuronal differentiation which is reversed by ibuprofen |
| topic | AIMP1 mutation differentiation actin ibuprofen |
| url | https://www.mdpi.com/2305-6320/7/5/25 |
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