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Ftd/Als Type 7–Associated Thr104Asn Mutation of CHMP2B Blunts Neuronal Process Elongation, and Is Recovered by Knockdown of Arf4, the Golgi Stress Regulator, in N1E-115 Cells
Shirai, R.; Cho, M.; Isogai, M.; Fukatsu, S.; Okabe, M.; Okawa, M.; Miyamoto, Y.; Torii, T.; Yamauchi, J. FTD/ALS Type 7-Associated Thr104Asn Mutation of CHMP2B Blunts Neuronal Process Elongation, and Is Recovered by Knockdown of Arf4, the Golgi Stress Regulator. Neurol. Int.2023, 15, 980-993.
Shirai, R.; Cho, M.; Isogai, M.; Fukatsu, S.; Okabe, M.; Okawa, M.; Miyamoto, Y.; Torii, T.; Yamauchi, J. FTD/ALS Type 7-Associated Thr104Asn Mutation of CHMP2B Blunts Neuronal Process Elongation, and Is Recovered by Knockdown of Arf4, the Golgi Stress Regulator. Neurol. Int. 2023, 15, 980-993.
Shirai, R.; Cho, M.; Isogai, M.; Fukatsu, S.; Okabe, M.; Okawa, M.; Miyamoto, Y.; Torii, T.; Yamauchi, J. FTD/ALS Type 7-Associated Thr104Asn Mutation of CHMP2B Blunts Neuronal Process Elongation, and Is Recovered by Knockdown of Arf4, the Golgi Stress Regulator. Neurol. Int.2023, 15, 980-993.
Shirai, R.; Cho, M.; Isogai, M.; Fukatsu, S.; Okabe, M.; Okawa, M.; Miyamoto, Y.; Torii, T.; Yamauchi, J. FTD/ALS Type 7-Associated Thr104Asn Mutation of CHMP2B Blunts Neuronal Process Elongation, and Is Recovered by Knockdown of Arf4, the Golgi Stress Regulator. Neurol. Int. 2023, 15, 980-993.
Abstract
Frontotemporal dementia and/or amyotrophic lateral sclerosis type 7 (FTD/ALS7) is an autosomal dominant neurodegenerative disorder characterized by the onset of ALS and/or FTD 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 patients with further other mutations have both phenotypes approximately equally; however, the reason why phenotypes differ depending on the position of the mutation is unknown. CHMP2B composes 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 of neuronal differentiation. The inhibitory phenotype was accompanied by changes in marker protein expression. It is noteworthy that CHMP2B with the T104N mutation but not its wild-type was preferentially accumulated in the Golgi body. Of the four major Golgi stress signaling pathways currently known, the pathway through Arf4, as 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 neuronal morphological differentiation by triggering Golgi stress signaling, revealing a possible therapeutic molecular target for recovering potential molecular and cellular phenotypes underlying FTD/ALS7.
Biology and Life Sciences, Neuroscience and Neurology
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