2019.04

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.chembiol.2024.03.001

Language：English   Publishing type：Research paper (scientific journal)  

DOI： https://doi.org/10.3389/fneur.2023.1211814

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for the Advancement of Science (AAAS)  

Intracranial aneurysms (IAs) are a high-risk factor for life-threatening subarachnoid hemorrhage. Their etiology, however, remains mostly unknown at present. We conducted screening for sporadic somatic mutations in 65 IA tissues (54 saccular and 11 fusiform aneurysms) and paired blood samples by whole-exome and targeted deep sequencing. We identified sporadic mutations in multiple signaling genes and examined their impact on downstream signaling pathways and gene expression in vitro and an arterial dilatation model in mice in vivo. We identified 16 genes that were mutated in at least one IA case and found that these mutations were highly prevalent (92%: 60 of 65 IAs) among all IA cases examined. In particular, mutations in six genes ( PDGFRB , AHNAK , OBSCN , RBM10 , CACNA1E , and OR5P3 ), many of which are linked to NF-κB signaling, were found in both fusiform and saccular IAs at a high prevalence (43% of all IA cases examined). We found that mutant PDGFRBs constitutively activated ERK and NF-κB signaling, enhanced cell motility, and induced inflammation-related gene expression in vitro. Spatial transcriptomics also detected similar changes in vessels from patients with IA. Furthermore, virus-mediated overexpression of a mutant PDGFRB induced a fusiform-like dilatation of the basilar artery in mice, which was blocked by systemic administration of the tyrosine kinase inhibitor sunitinib. Collectively, this study reveals a high prevalence of somatic mutations in NF-κB signaling pathway–related genes in both fusiform and saccular IAs and opens a new avenue of research for developing pharmacological interventions.

DOI： 10.1126/scitranslmed.abq7721

Language：English   Publishing type：Research paper (scientific journal)  

SPG80 is a neurodegenerative disorder characterized by a pure type of juvenile-onset hereditary spastic paraplegia and is caused by a heterozygous mutation of the UBAP1 (ubiquitin-associated protein 1) gene. UBAP1 is one of the subunits of the endosomal sorting complex required for transport I and plays a role in endosome sorting by binding to ubiquitin-tagged proteins. In this study, we generated novel Ubap1+/E176Efx23 knock-in mice, in which the SOUBA domain of Ubap1 was completely deleted with the UMA domain being intact, as an animal model of SPG80. The knock-in mice with this heterozygous Ubap1 truncated mutation appeared normal at birth, but they developed progressive hind limb dysfunction several months later. Molecular pathologically, loss of neurons in the spinal cord and accumulation of ubiquitinated proteins were observed in Ubap1+/E176Efx23 knock-in mice. In addition, changes in the distributions of Rab5 and Rab7 in the spinal cord suggest that this mutation in Ubap1 disturbs endosome-mediated vesicular trafficking. This is the first report of a mouse model that reproduces the phenotype of SPG80. Our knock-in mice may provide a clue for understanding the molecular pathogenesis underlying UBAP1-related HSP and screening of therapeutic agents.

DOI： 10.1038/s10038-022-01073-6

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：wolters kluwer  

<sec><title>Background and Objectives</title>Variations in <italic>SLC9A6</italic> cause the X-linked neurologic disorder Christianson syndrome in males. Meanwhile, female carriers with <italic>SLC9A6</italic> variations may remain asymptomatic or develop intellectual disability, behavioral problems, and psychiatric illnesses. Only a few female carriers have been reported to have associated atypical parkinsonism in late life.

</sec><sec><title>Methods</title>We present a Japanese family with a novel <italic>SLC9A6</italic> variation identified by quad whole-exome sequencing analysis and a reverse phenotyping strategy. The molecular and cellular impacts of the W89R variation in vitro were examined.

</sec><sec><title>Results</title>The missense variation (c.265T&gt;C, p.Trp89Arg) in <italic>SLC9A6</italic> cosegregated with atypical parkinsonism and intellectual disability in female carriers of this family. The female carriers in this family presented with bradykinesia, rigidity, and tremor, predominately on the right side. We found that the W89R variation changed membrane traffic of NHE6-harboring vesicles, indicating potential involvement in the disease pathogenesis.

</sec><sec><title>Discussion</title>This study might have revealed an example of a monogenic origin of atypical parkinsonism in females with <italic>SLC9A6</italic> variations and draw attention to this understudied female-specific phenotype in clinical practice.

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DOI： 10.1212/NXG.0000000000000651

Event date： 2024.3

Language：Japanese   Presentation type：Poster presentation  

File： MS2_技術交流会要旨_金.docx

Event date： 2024.3

Language：English   Presentation type：Poster presentation  

Event date： 2024.2

Language：English   Presentation type：Oral presentation(general)  

Event date： 2023.8

Language：English   Presentation type：Oral presentation(general)  

File： 日本神経科学会2023_金然正.docx

Event date： 2023.7

Language：English   Presentation type：Poster presentation  

Applicant：国立大学法人山梨大学

Application no：特願2023-036623  Date applied：2023.3

Country of applicant：Domestic  

本発明は、従来における前記諸問題を解決し、以下の目的を達成することを課題とする
。即ち、本発明は、ＰＬＣの活性化を特異的に制御できる光駆動型システムを構築するた
めの分子を提供する。