RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS

Shimizu, Mikito; Shiraishi, Naoyuki; Tada, Satoru; Sasaki, Tsutomu; Beck, Goichi; Nagano, Seiichi; Kinoshita, Makoto; Sumi, Hisae; Sugimoto, Tomoyuki; Ishida, Yoko; Koda, Toru; Ishikura, Teruyuki; Sugiyama, Yasuko; Kihara, Keigo; Kanakura, Minami; Nakajima, Tsuneo; Takeda, Shuko; Takahashi, Masanori; Yamashita, Toshihide; Okuno, Tatsusada; Mochizuki, Hideki

doi:https://doi.org/10.1126/sciadv.adg3193

RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS

Shimizu, Mikito; Shiraishi, Naoyuki; Tada, Satoru et al.

Science Advances, 2023, 9(47), 686

Number of Access:3,200（2025-07-18 09:49 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/93231

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Title	RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS
Creator	NRID 1000030817507 1000030817507 researchmap permalink M_Shimizu_4313 M_Shimizu_4313 CreatorName Shimizu, Mikito
	NRID 1000010882285 1000010882285 CreatorName Shiraishi, Naoyuki
	NRID 1000070626530 1000070626530 CreatorName Tada, Satoru
	NRID 1000020534879 1000020534879 ORCID 0000-0001-8726-978X 0000-0001-8726-978X researchmap permalink tsutomusasaki1111 tsutomusasaki1111 Scopus Author ID 7407394272 7407394272 CreatorName Sasaki, Tsutomu
	NRID 1000020626353 1000020626353 researchmap permalink beck-neuro beck-neuro Scopus Author ID 53867774800 53867774800 CreatorName Beck, Goichi
	NRID 1000040362727 1000040362727 researchmap permalink read0106301 read0106301 Scopus Author ID 7103321284 7103321284 CreatorName Nagano, Seiichi
	NRID 1000010573222 1000010573222 researchmap permalink 101101101101101 101101101101101 Scopus Author ID 55363330100 55363330100 CreatorName Kinoshita, Makoto
	NRID 1000030403059 1000030403059 CreatorName Sumi, Hisae
	NRID 1000070324829 1000070324829 CreatorName Sugimoto, Tomoyuki
	CreatorName Ishida, Yoko
	NRID 1000070626134 1000070626134 researchmap permalink neurol neurol Scopus Author ID 55805648600 55805648600 CreatorName Koda, Toru
	NRID 1000080838524 1000080838524 CreatorName Ishikura, Teruyuki
	CreatorName Sugiyama, Yasuko
	CreatorName Kihara, Keigo
	CreatorName Kanakura, Minami
	NRID 1000010858525 1000010858525 researchmap permalink ntsuneo ntsuneo CreatorName Nakajima, Tsuneo
	NRID 1000050784708 1000050784708 researchmap permalink shukotakeda shukotakeda Scopus Author ID 23475751800 23475751800 CreatorName Takeda, Shuko
	NRID 1000020359847 1000020359847 researchmap permalink mtakahas mtakahas Scopus Author ID 15038719500 15038719500 CreatorName Takahashi, Masanori
	NRID 1000010301269 1000010301269 ORCID 0000-0003-4559-7018 0000-0003-4559-7018 researchmap permalink ToshihideYamashita ToshihideYamashita Scopus Author ID 35479670200 35479670200 CreatorName Yamashita, Toshihide
	NRID 1000000464248 1000000464248 researchmap permalink neuroimmunology neuroimmunology Scopus Author ID 9736132000 9736132000 CreatorName Okuno, Tatsusada
	NRID 1000090230044 1000090230044 ORCID 0000-0002-0874-7542 0000-0002-0874-7542 researchmap permalink read0207787 read0207787 Scopus Author ID 7202006099 7202006099 CreatorName Mochizuki, Hideki
Description	Shimizu Mikito, Shiraishi Naoyuki, Tada Satoru, et al. RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS. Science Advances 9, 686 (2023); https://doi.org/10.1126/sciadv.adg3193.
Abstract	Repulsive guidance molecule A (RGMa) was originally identified as a neuronal growth cone–collapsing factor. Previous reports have demonstrated the multifunctional roles of RGMa mediated by neogenin1. However, the pathogenic involvement of RGMa in amyotrophic lateral sclerosis (ALS) remains unclear. Here, we demonstrated that RGMa concentration was elevated in the cerebrospinal fluid of both patients with ALS and transgenic mice overexpressing the mutant human superoxide dismutase1 (mSOD1 mice). Treatment with humanized anti-RGMa monoclonal antibody ameliorated the clinical symptoms in mSOD1 mice. Histochemical analysis revealed that the anti-RGMa antibody significantly decreased mutant SOD1 protein accumulation in the motor neurons of mSOD1 mice via inhibition of actin depolymerization. In vitro analysis revealed that the anti-RGMa antibody inhibited the cellular uptake of the mutant SOD1 protein, presumably by reinforcing the neuronal actin barrier. Collectively, these data suggest that RGMa leads to the collapse of the neuronal actin barrier and promotes aberrant protein deposition, resulting in exacerbation of the ALS pathology.
Publisher	American Association for the Advancement of Science (AAAS)
Source Title	Science Advances
Volume (Issue)	9(47)
Page	686
Date of Issued	2023-11-24
Language	English
Handle URL	https://hdl.handle.net/11094/93231
eISSN	23752548
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1126/sciadv.adg3193
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Science Advances. 2023, 9(47), p. 686
DC.title	RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS
DC.creator	Shimizu, Mikito
	Shiraishi, Naoyuki
	Tada, Satoru
	Sasaki, Tsutomu
	Beck, Goichi
	Nagano, Seiichi
	Kinoshita, Makoto
	Sumi, Hisae
	Sugimoto, Tomoyuki
	Ishida, Yoko
	Koda, Toru
	Ishikura, Teruyuki
	Sugiyama, Yasuko
	Kihara, Keigo
	Kanakura, Minami
	Nakajima, Tsuneo
	Takeda, Shuko
	Takahashi, Masanori
	Yamashita, Toshihide
	Okuno, Tatsusada
	Mochizuki, Hideki
DC.publisher	American Association for the Advancement of Science (AAAS)
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2023-11-24
DC.identifier	https://doi.org/10.1126/sciadv.adg3193
DC.description	Shimizu Mikito, Shiraishi Naoyuki, Tada Satoru, et al. RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS. Science Advances 9, 686 (2023); https://doi.org/10.1126/sciadv.adg3193.
DCTERMS.abstract	Repulsive guidance molecule A (RGMa) was originally identified as a neuronal growth cone–collapsing factor. Previous reports have demonstrated the multifunctional roles of RGMa mediated by neogenin1. However, the pathogenic involvement of RGMa in amyotrophic lateral sclerosis (ALS) remains unclear. Here, we demonstrated that RGMa concentration was elevated in the cerebrospinal fluid of both patients with ALS and transgenic mice overexpressing the mutant human superoxide dismutase1 (mSOD1 mice). Treatment with humanized anti-RGMa monoclonal antibody ameliorated the clinical symptoms in mSOD1 mice. Histochemical analysis revealed that the anti-RGMa antibody significantly decreased mutant SOD1 protein accumulation in the motor neurons of mSOD1 mice via inhibition of actin depolymerization. In vitro analysis revealed that the anti-RGMa antibody inhibited the cellular uptake of the mutant SOD1 protein, presumably by reinforcing the neuronal actin barrier. Collectively, these data suggest that RGMa leads to the collapse of the neuronal actin barrier and promotes aberrant protein deposition, resulting in exacerbation of the ALS pathology.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	93231
citation_title	RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS
citation_author	Shimizu, Mikito
	Shiraishi, Naoyuki
	Tada, Satoru
	Sasaki, Tsutomu
	Beck, Goichi
	Nagano, Seiichi
	Kinoshita, Makoto
	Sumi, Hisae
	Sugimoto, Tomoyuki
	Ishida, Yoko
	Koda, Toru
	Ishikura, Teruyuki
	Sugiyama, Yasuko
	Kihara, Keigo
	Kanakura, Minami
	Nakajima, Tsuneo
	Takeda, Shuko
	Takahashi, Masanori
	Yamashita, Toshihide
	Okuno, Tatsusada
	Mochizuki, Hideki
citation_publisher	American Association for the Advancement of Science (AAAS)
citation_language	English
citation_date	2023-11-24
citation_journal_title	Science Advances
citation_volume	9
citation_issue	47
citation_firstpage	686
citation_doi	https://doi.org/10.1126/sciadv.adg3193
citation_public_url	https://hdl.handle.net/11094/93231

RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS

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