Modulating Golgi Stress Signaling Ameliorates Cell Morphological Phenotypes Induced by CHMP2B with Frontotemporal Dementia-Associated p.Asp148Tyr
Some charged multivesicular body protein 2B (CHMP2B) mutations are associated with autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 7 (FTDALS7). The main aim of this study is to clarify the relationship between the expression of mutated CHMP2B pr...
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MDPI AG
2024-02-01
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| Series: | Current Issues in Molecular Biology |
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| Online Access: | https://www.mdpi.com/1467-3045/46/2/90 |
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| author | Shoya Fukatsu Maho Okawa Miyu Okabe Mizuka Cho Mikinori Isogai Takanori Yokoi Remina Shirai Hiroaki Oizumi Masahiro Yamamoto Katsuya Ohbuchi Yuki Miyamoto Junji Yamauchi |
| author_facet | Shoya Fukatsu Maho Okawa Miyu Okabe Mizuka Cho Mikinori Isogai Takanori Yokoi Remina Shirai Hiroaki Oizumi Masahiro Yamamoto Katsuya Ohbuchi Yuki Miyamoto Junji Yamauchi |
| author_sort | Shoya Fukatsu |
| collection | DOAJ |
| description | Some charged multivesicular body protein 2B (CHMP2B) mutations are associated with autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 7 (FTDALS7). The main aim of this study is to clarify the relationship between the expression of mutated CHMP2B protein displaying FTD symptoms and defective neuronal differentiation. First, we illustrate that the expression of CHMP2B with the Asp148Tyr (D148Y) mutation, which preferentially displays FTD phenotypes, blunts neurite process elongation in rat primary cortical neurons. Similar results were observed in the N1E-115 cell line, a model that undergoes neurite elongation. Second, these effects were also accompanied by changes in neuronal differentiation marker protein expression. Third, wild-type CHMP2B protein was indeed localized in the endosomal sorting complexes required to transport (ESCRT)-like structures throughout the cytoplasm. In contrast, CHMP2B with the D148Y mutation exhibited aggregation-like structures and accumulated in the Golgi body. Fourth, among currently known Golgi stress regulators, the expression levels of Hsp47, which has protective effects on the Golgi body, were decreased in cells expressing CHMP2B with the D148Y mutation. Fifth, Arf4, another Golgi stress-signaling molecule, was increased in mutant-expressing cells. Finally, when transfecting Hsp47 or knocking down Arf4 with small interfering (si)RNA, cellular phenotypes in mutant-expressing cells were recovered. These results suggest that CHMP2B with the D148Y mutation, acting through Golgi stress signaling, is negatively involved in the regulation of neuronal cell morphological differentiation, providing evidence that a molecule controlling Golgi stress may be one of the potential FTD therapeutic targets at the molecular and cellular levels. |
| first_indexed | 2024-03-07T22:37:56Z |
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| language | English |
| last_indexed | 2024-03-07T22:37:56Z |
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| series | Current Issues in Molecular Biology |
| spelling | doaj.art-b1a5e5bac9e849a5b02a906e028154b32024-02-23T15:12:38ZengMDPI AGCurrent Issues in Molecular Biology1467-30371467-30452024-02-014621398141210.3390/cimb46020090Modulating Golgi Stress Signaling Ameliorates Cell Morphological Phenotypes Induced by CHMP2B with Frontotemporal Dementia-Associated p.Asp148TyrShoya Fukatsu0Maho Okawa1Miyu Okabe2Mizuka Cho3Mikinori Isogai4Takanori Yokoi5Remina Shirai6Hiroaki Oizumi7Masahiro Yamamoto8Katsuya Ohbuchi9Yuki Miyamoto10Junji Yamauchi11Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, JapanTsumura Research Laboratories, Tsumura & Co., Inashiki 200-1192, JapanTsumura Research Laboratories, Tsumura & Co., Inashiki 200-1192, JapanTsumura Research Laboratories, Tsumura & Co., Inashiki 200-1192, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, JapanSome charged multivesicular body protein 2B (CHMP2B) mutations are associated with autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 7 (FTDALS7). The main aim of this study is to clarify the relationship between the expression of mutated CHMP2B protein displaying FTD symptoms and defective neuronal differentiation. First, we illustrate that the expression of CHMP2B with the Asp148Tyr (D148Y) mutation, which preferentially displays FTD phenotypes, blunts neurite process elongation in rat primary cortical neurons. Similar results were observed in the N1E-115 cell line, a model that undergoes neurite elongation. Second, these effects were also accompanied by changes in neuronal differentiation marker protein expression. Third, wild-type CHMP2B protein was indeed localized in the endosomal sorting complexes required to transport (ESCRT)-like structures throughout the cytoplasm. In contrast, CHMP2B with the D148Y mutation exhibited aggregation-like structures and accumulated in the Golgi body. Fourth, among currently known Golgi stress regulators, the expression levels of Hsp47, which has protective effects on the Golgi body, were decreased in cells expressing CHMP2B with the D148Y mutation. Fifth, Arf4, another Golgi stress-signaling molecule, was increased in mutant-expressing cells. Finally, when transfecting Hsp47 or knocking down Arf4 with small interfering (si)RNA, cellular phenotypes in mutant-expressing cells were recovered. These results suggest that CHMP2B with the D148Y mutation, acting through Golgi stress signaling, is negatively involved in the regulation of neuronal cell morphological differentiation, providing evidence that a molecule controlling Golgi stress may be one of the potential FTD therapeutic targets at the molecular and cellular levels.https://www.mdpi.com/1467-3045/46/2/90CHMP2BGolgi stressHsp47Arf4differentiation |
| spellingShingle | Shoya Fukatsu Maho Okawa Miyu Okabe Mizuka Cho Mikinori Isogai Takanori Yokoi Remina Shirai Hiroaki Oizumi Masahiro Yamamoto Katsuya Ohbuchi Yuki Miyamoto Junji Yamauchi Modulating Golgi Stress Signaling Ameliorates Cell Morphological Phenotypes Induced by CHMP2B with Frontotemporal Dementia-Associated p.Asp148Tyr Current Issues in Molecular Biology CHMP2B Golgi stress Hsp47 Arf4 differentiation |
| title | Modulating Golgi Stress Signaling Ameliorates Cell Morphological Phenotypes Induced by CHMP2B with Frontotemporal Dementia-Associated p.Asp148Tyr |
| title_full | Modulating Golgi Stress Signaling Ameliorates Cell Morphological Phenotypes Induced by CHMP2B with Frontotemporal Dementia-Associated p.Asp148Tyr |
| title_fullStr | Modulating Golgi Stress Signaling Ameliorates Cell Morphological Phenotypes Induced by CHMP2B with Frontotemporal Dementia-Associated p.Asp148Tyr |
| title_full_unstemmed | Modulating Golgi Stress Signaling Ameliorates Cell Morphological Phenotypes Induced by CHMP2B with Frontotemporal Dementia-Associated p.Asp148Tyr |
| title_short | Modulating Golgi Stress Signaling Ameliorates Cell Morphological Phenotypes Induced by CHMP2B with Frontotemporal Dementia-Associated p.Asp148Tyr |
| title_sort | modulating golgi stress signaling ameliorates cell morphological phenotypes induced by chmp2b with frontotemporal dementia associated p asp148tyr |
| topic | CHMP2B Golgi stress Hsp47 Arf4 differentiation |
| url | https://www.mdpi.com/1467-3045/46/2/90 |
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