FTD/ALS Type 7-Associated Thr104Asn Mutation of CHMP2B Blunts Neuronal Process Elongation, and Is Recovered by Knockdown of Arf4, the Golgi Stress Regulator
Frontotemporal dementia and/or amyotrophic lateral sclerosis type 7 (FTD/ALS7) is an autosomal dominant neurodegenerative disorder characterized by the onset of FTD and/or ALS, mainly in adulthood. Patients with some types of mutations, including the Thr104Asn (T104N) mutation of charged multivesicu...
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MDPI AG
2023-08-01
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| author | Remina Shirai Mizuka Cho Mikinori Isogai Shoya Fukatsu Miyu Okabe Maho Okawa Yuki Miyamoto Tomohiro Torii Junji Yamauchi |
| author_facet | Remina Shirai Mizuka Cho Mikinori Isogai Shoya Fukatsu Miyu Okabe Maho Okawa Yuki Miyamoto Tomohiro Torii Junji Yamauchi |
| author_sort | Remina Shirai |
| collection | DOAJ |
| description | Frontotemporal dementia and/or amyotrophic lateral sclerosis type 7 (FTD/ALS7) is an autosomal dominant neurodegenerative disorder characterized by the onset of FTD and/or ALS, mainly in adulthood. Patients with some types of mutations, including the Thr104Asn (T104N) mutation of charged multivesicular body protein 2B (CHMP2B), have predominantly ALS phenotypes, whereas patients with other mutations have predominantly FTD phenotypes. A few mutations result in patients having both phenotypes approximately equally; however, the reason why phenotypes differ depending on the position of the mutation is unknown. CHMP2B comprises one part of the endosomal sorting complexes required for transport (ESCRT), specifically ESCRT-III, in the cytoplasm. We describe here, for the first time, that CHMP2B with the T104N mutation inhibits neuronal process elongation in the N1E-115 cell line, a model line undergoing neuronal differentiation. This inhibitory phenotype was accompanied by changes in marker protein expression. Of note, CHMP2B with the T104N mutation, but not the wild-type form, was preferentially accumulated in the Golgi body. Of the four major Golgi stress signaling pathways currently known, the pathway through Arf4, the small GTPase, was specifically upregulated in cells expressing CHMP2B with the T104N mutation. Conversely, knockdown of Arf4 with the cognate small interfering (si)RNA recovered the neuronal process elongation inhibited by the T104N mutation. These results suggest that the T104N mutation of CHMP2B inhibits morphological differentiation by triggering Golgi stress signaling, revealing a possible therapeutic molecular target for recovering potential molecular and cellular phenotypes underlying FTD/ALS7. |
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| spelling | doaj.art-e1cc3c446a9c48fab23714fac17c5abe2023-11-19T12:15:53ZengMDPI AGNeurology International2035-83772023-08-0115398099310.3390/neurolint15030063FTD/ALS Type 7-Associated Thr104Asn Mutation of CHMP2B Blunts Neuronal Process Elongation, and Is Recovered by Knockdown of Arf4, the Golgi Stress RegulatorRemina Shirai0Mizuka Cho1Mikinori Isogai2Shoya Fukatsu3Miyu Okabe4Maho Okawa5Yuki Miyamoto6Tomohiro Torii7Junji Yamauchi8Laboratory 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, JapanLaboratory of Ion Channel Pathophysiology, Doshisha University Graduate School of Brain Science, Kyoto 610-0394, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, JapanFrontotemporal dementia and/or amyotrophic lateral sclerosis type 7 (FTD/ALS7) is an autosomal dominant neurodegenerative disorder characterized by the onset of FTD and/or ALS, mainly in adulthood. Patients with some types of mutations, including the Thr104Asn (T104N) mutation of charged multivesicular body protein 2B (CHMP2B), have predominantly ALS phenotypes, whereas patients with other mutations have predominantly FTD phenotypes. A few mutations result in patients having both phenotypes approximately equally; however, the reason why phenotypes differ depending on the position of the mutation is unknown. CHMP2B comprises one part of the endosomal sorting complexes required for transport (ESCRT), specifically ESCRT-III, in the cytoplasm. We describe here, for the first time, that CHMP2B with the T104N mutation inhibits neuronal process elongation in the N1E-115 cell line, a model line undergoing neuronal differentiation. This inhibitory phenotype was accompanied by changes in marker protein expression. Of note, CHMP2B with the T104N mutation, but not the wild-type form, was preferentially accumulated in the Golgi body. Of the four major Golgi stress signaling pathways currently known, the pathway through Arf4, the small GTPase, was specifically upregulated in cells expressing CHMP2B with the T104N mutation. Conversely, knockdown of Arf4 with the cognate small interfering (si)RNA recovered the neuronal process elongation inhibited by the T104N mutation. These results suggest that the T104N mutation of CHMP2B inhibits morphological differentiation by triggering Golgi stress signaling, revealing a possible therapeutic molecular target for recovering potential molecular and cellular phenotypes underlying FTD/ALS7.https://www.mdpi.com/2035-8377/15/3/63CHMP2BN1E-115 cellneuronal differentiationArf4Golgi stress |
| spellingShingle | Remina Shirai Mizuka Cho Mikinori Isogai Shoya Fukatsu Miyu Okabe Maho Okawa Yuki Miyamoto Tomohiro Torii Junji Yamauchi FTD/ALS Type 7-Associated Thr104Asn Mutation of CHMP2B Blunts Neuronal Process Elongation, and Is Recovered by Knockdown of Arf4, the Golgi Stress Regulator Neurology International CHMP2B N1E-115 cell neuronal differentiation Arf4 Golgi stress |
| title | FTD/ALS Type 7-Associated Thr104Asn Mutation of CHMP2B Blunts Neuronal Process Elongation, and Is Recovered by Knockdown of Arf4, the Golgi Stress Regulator |
| title_full | FTD/ALS Type 7-Associated Thr104Asn Mutation of CHMP2B Blunts Neuronal Process Elongation, and Is Recovered by Knockdown of Arf4, the Golgi Stress Regulator |
| title_fullStr | FTD/ALS Type 7-Associated Thr104Asn Mutation of CHMP2B Blunts Neuronal Process Elongation, and Is Recovered by Knockdown of Arf4, the Golgi Stress Regulator |
| title_full_unstemmed | FTD/ALS Type 7-Associated Thr104Asn Mutation of CHMP2B Blunts Neuronal Process Elongation, and Is Recovered by Knockdown of Arf4, the Golgi Stress Regulator |
| title_short | FTD/ALS Type 7-Associated Thr104Asn Mutation of CHMP2B Blunts Neuronal Process Elongation, and Is Recovered by Knockdown of Arf4, the Golgi Stress Regulator |
| title_sort | ftd als type 7 associated thr104asn mutation of chmp2b blunts neuronal process elongation and is recovered by knockdown of arf4 the golgi stress regulator |
| topic | CHMP2B N1E-115 cell neuronal differentiation Arf4 Golgi stress |
| url | https://www.mdpi.com/2035-8377/15/3/63 |
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