FBXL17/spastin axis as a novel therapeutic target of hereditary spastic paraplegia

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dc.contributor.authorHyun Mi Kang-
dc.contributor.authorDae Hun Kim-
dc.contributor.authorMijin Kim-
dc.contributor.authorYoohong Min-
dc.contributor.authorBohyeon Jeong-
dc.contributor.authorKyung Hee Noh-
dc.contributor.authorDa Yong Lee-
dc.contributor.authorHyun-Soo Cho-
dc.contributor.authorNam-Soon Kim-
dc.contributor.authorCho-Rok Jung-
dc.contributor.authorJung Hwa Lim-
dc.date.accessioned2022-07-29T01:06:37Z-
dc.date.available2022-07-29T01:06:37Z-
dc.date.issued2022-
dc.identifier.issn2045-3701-
dc.identifier.urihttps://oak.kribb.re.kr/handle/201005/30102-
dc.description.abstractBackground: Spastin significantly influences microtubule regulation in neurons and is implicated in the pathogenesis of hereditary spastic paraplegia (HSP). However, post-translational regulation of the spastin protein remains nebulous. The association between E3 ubiquitin ligase and spastin provides a potential therapeutic strategy. Results: As evidenced by protein chip analysis, FBXL17 inversely correlated with SPAST-M1 at the protein level in vitro and, also in vivo during embryonic developmental stage. SPAST-M1 protein interacted with FBXL17 specifically via the BTB domain at the N-terminus of SPAST-M1. The SCFFBXL17 E3 ubiquitin ligase complex degraded SPAST-M1 protein in the nuclear fraction in a proteasome-dependent manner. SPAST phosphorylation occurred only in the cytoplasmic fraction by CK2 and was involved in poly-ubiquitination. Inhibition of SCFFBXL17 E3 ubiquitin ligase by small chemical and FBXL17 shRNA decreased proteasome-dependent degradation of SPAST-M1 and induced axonal extension. The SPAST Y52C mutant, harboring abnormality in BTB domain could not interact with FBXL17, thereby escaping protein regulation by the SCFFBXL17 E3 ubiquitin ligase complex, resulting in loss of functionality with aberrant quantity. Although this mutant showed shortening of axonal outgrowth, low rate proliferation, and poor differentiation capacity in a 3D model, this phenotype was rescued by inhibiting SCFFBXL17 E3 ubiquitin ligase. Conclusions: We discovered that a novel pathway, FBXL17-SPAST was involved in pathogenicity of HSP by the loss of function and the quantitative regulation. This result suggested that targeting FBXL17 could provide new insight into HSP therapeutics.-
dc.publisherSpringer-BMC-
dc.titleFBXL17/spastin axis as a novel therapeutic target of hereditary spastic paraplegia-
dc.title.alternativeFBXL17/spastin axis as a novel therapeutic target of hereditary spastic paraplegia-
dc.typeArticle-
dc.citation.titleCell and Bioscience-
dc.citation.number0-
dc.citation.endPage110-
dc.citation.startPage110-
dc.citation.volume12-
dc.contributor.affiliatedAuthorHyun Mi Kang-
dc.contributor.affiliatedAuthorDae Hun Kim-
dc.contributor.affiliatedAuthorMijin Kim-
dc.contributor.affiliatedAuthorYoohong Min-
dc.contributor.affiliatedAuthorBohyeon Jeong-
dc.contributor.affiliatedAuthorKyung Hee Noh-
dc.contributor.affiliatedAuthorDa Yong Lee-
dc.contributor.affiliatedAuthorHyun-Soo Cho-
dc.contributor.affiliatedAuthorNam-Soon Kim-
dc.contributor.affiliatedAuthorCho-Rok Jung-
dc.contributor.affiliatedAuthorJung Hwa Lim-
dc.contributor.alternativeName강현미-
dc.contributor.alternativeName김대훈-
dc.contributor.alternativeName김미진-
dc.contributor.alternativeName민유홍-
dc.contributor.alternativeName정보현-
dc.contributor.alternativeName노경희-
dc.contributor.alternativeName이다용-
dc.contributor.alternativeName조현수-
dc.contributor.alternativeName김남순-
dc.contributor.alternativeName정초록-
dc.contributor.alternativeName임정화-
dc.identifier.bibliographicCitationCell and Bioscience, vol. 12, pp. 110-110-
dc.identifier.doi10.1186/s13578-022-00851-1-
dc.subject.keywordSPAST-
dc.subject.keywordE3 ubiquitin ligase-
dc.subject.keywordSCF complex-
dc.subject.keywordFBXL17-
dc.subject.keywordHereditary spastic paraplegia-
dc.subject.localSPAST-
dc.subject.localE3 ubiquitinligase-
dc.subject.localE3 ubiquitin ligase-
dc.subject.localSCF complex-
dc.subject.localFBXL17-
dc.subject.localHereditary spastic paraplegia-
dc.description.journalClassY-
Appears in Collections:
Division of Research on National Challenges > Stem Cell Convergenece Research Center > 1. Journal Articles
Division of Biomedical Research > Rare Disease Research Center > 1. Journal Articles
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