慶應義塾研究者情報データベース

経歴 【 表示 ／ 非表示 】

経歴 【 表示 ／ 非表示 】

• 2003年04月

  -

  2011年04月

  慶應義塾大学　, 医学部　生理学教室, 研究員

• 2011年05月

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  2018年10月

  理化学研究所, 免疫・アレルギー科学総合研究センター, テクニカルスタッフI

• 2018年11月

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  2024年03月

  慶應義塾大学　, 医学部　生理学教室, 研究員

• 2024年04月

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  継続中

  慶應義塾大学　, 再生医療リサーチセンター, 研究員

論文 【 表示 ／ 非表示 】

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• Diagnostic potential of cryptic exon-derived peptides in serum extracellular vesicles for sporadic amyotrophic lateral sclerosis

  Takahashi K., Kato C., Ueda K., Nakamura S., Ozawa F., Moritoki N., Shibata S., Takahashi S., Morimoto S., Okano H.

  Inflammation and Regeneration 46 （ 1 ）  2026年12月

  ISSN  18809693

  　概要を見る

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration and loss of upper and lower motor neurons, with approximately 90% of cases being sporadic (sporadic ALS, SALS). A reliable diagnostic biomarker remains an unmet clinical need in SALS, with misdiagnosis and diagnostic delay hindering early management. The mislocalization of the RNA-binding protein TDP-43 (encoded by TARDBP), a pathological hallmark of SALS, could lead to aberrant splicing that produces transcripts with cryptic exons and, consequently, cryptic peptides. This study proposes cryptic peptides in serum extracellular vesicles as a novel candidate diagnostic biomarker of SALS. We included 10 healthy controls and 20 patients with SALS and quantified cryptic peptides predicted from cryptic exon sequences using mass spectrometry-based proteomics. Cryptic peptides from four proteins (RANBP1, IGLON5, ACTN1, ALPK2) were detected in participants, with the IGLON5 cryptic peptide detected significantly more frequently in SALS than in HC (adjusted P = 0.044). The number of detected cryptic peptides classified SALS and healthy controls with acceptable performance (area under the curve = 0.82). In conclusion, cryptic peptides could have diagnostic performance for SALS, warranting further validation.

  • Access to Document (DOI)

• A genome-wide association study identifies the GPM6A locus associated with age at onset in ALS

  Nakamura R., Tohnai G., Atsuta N., Matsuda Y., Morimoto S., Ito D., Katsuno M., Izumi Y., Morita M., Iwata I., Yabe I., Nakazato T., Hattori N., Hirayama T., Kano O., Tamura A., Suzuki N., Aoki M., Shibuya K., Kuwabara S., Oda M., Hashimoto R., Aiba I., Ishihara T., Onodera O., Yamashita T., Ishiura H., Bokuda K., Shimizu T., Ikeda Y., Hasegawa K., Tanaka F., Yokota T., Kanai K., Noto Y.I., Kaji R., Watanabe H., Konishi T., Hasegawa M., Fukaya H., Niwa J.I., Doyu M., Okada Y., Nakamura S., Ozawa F., Okano H., Nakatochi M., Sobue G.

  Communications Biology 8 （ 1 ）  2025年12月

  　概要を見る

  Amyotrophic lateral sclerosis (ALS) exhibits considerable clinical variability, such as differences in age at onset (AAO). Multiple factors, including genetic factors, may underlie this variability; however, the specific determinants remain unclear. To identify genes affecting AAO, we have conducted a genome-wide association study in Japanese patients with ALS (discovery cohort: n = 1808; replication cohort: n = 207). Here, we show that the minor A allele of rs113161727 at the ADAM29-GPM6A locus is associated with a younger AAO in the discovery cohort (effect, -4.27 years; p = 4.60 × 10^-8); this finding has been confirmed in the replication cohort (p = 0.0068) and meta-analysis (p = 1.08 × 10⁻⁹). Among 65 ALS patients with a SOD1 mutation, the AAO has been found to be 10.2 years younger in those with the A allele than in those without it (p = 0.002). This variant correlates with GPM6A upregulation in iPSC-derived motor neurons, suggesting GPM6A as a candidate AAO modifier. Overall, our study highlights the impact of genetic modifiers on ALS heterogeneity and provides a potential target for delaying disease onset.

  • Access to Document (DOI)

• Protocol for the induction of human spinal motor neurons from human induced pluripotent stem cells for studying amyotrophic lateral sclerosis

  Setsu S., Morimoto S., Nakamura S., Ozawa F., Okano H.

  STAR Protocols 6 （ 3 ）  2025年09月

  　概要を見る

  Here, we present a protocol for inducing spinal lower motor neurons (LMNs) from human induced pluripotent stem cells (iPSCs). We describe steps for preparation of a chemically induced transitional state (CTraS), transduction with Sendai virus, and LMN differentiation and maintenance. We then detail procedures for live imaging for single-cell-based survival analysis and neurite length of LMNs using BioStation and immunocytochemistry for induction efficiency check. This protocol is optimized for amyotrophic lateral sclerosis (ALS) research and large-scale screening. For complete details on the use and execution of this protocol, please refer to Setsu et al.¹

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• Swift induction of human spinal lower motor neurons and robust ALS cell screening via single-cell imaging

  Setsu S., Morimoto S., Nakamura S., Ozawa F., Utami K.H., Nishiyama A., Suzuki N., Aoki M., Takeshita Y., Tomari Y., Okano H.

  Stem Cell Reports 20 （ 1 ）  2025年01月

  　概要を見る

  This study introduces a novel method for rapidly and efficiently inducing human spinal lower motor neurons (LMNs) from induced pluripotent stem cells (iPSCs) to eventually elucidate the pathomechanisms of amyotrophic lateral sclerosis (ALS) and facilitate drug screening. Previous methods were limited by low induction efficiency, poor LMN purity, or labor-intensive induction and evaluation processes. Our protocol overcomes these challenges, achieving around 80% induction efficiency within just two weeks by combining a small molecule-based approach with transcription factor transduction. Moreover, to exclude non-LMN cells from the analysis, we utilized time-lapse microscopy and machine learning to analyze the morphology and viability of iPSC-derived LMNs on a single-cell basis, establishing an effective pathophysiological evaluation system. This rapid, efficient, and streamlined protocol, along with our single-cell-based evaluation method, enables large-scale analysis and drug screening using iPSC-derived motor neurons.

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• Proteomic insights into extracellular vesicles in ALS for therapeutic potential of Ropinirole and biomarker discovery

  Kato C., Ueda K., Morimoto S., Takahashi S., Nakamura S., Ozawa F., Ito D., Daté Y., Okada K., Kobayashi N., Nakahara J., Okano H.

  Inflammation and Regeneration 44 （ 1 ）  2024年12月

  　概要を見る

  Background: Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs. Methods: We collected serum and CSF at fixed intervals from ten controls and from 20 SALS patients participating in the ROPALS trial. Comprehensive proteomic analysis of EVs, extracted from these samples, was conducted using liquid chromatography/mass spectrometer (LC/MS). Furthermore, we generated iPSC-derived astrocytes (iPasts) and performed RNA sequencing on astrocytes with or without ROPI treatment. Results: The findings revealed notable disparities yet high congruity in sEVs and cEVs protein profiles concerning disease status, time and ROPI administration. In SALS, both sEVs and cEVs presented elevated levels of inflammation-related proteins but reduced levels associated with unfolded protein response (UPR). These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale (ALSFRS-R) at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to UPR in SALS, proposing an anti-ALS impact on EV protein profiles. Reverse translational research using iPasts indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. We have also identified biomarkers that predict diagnosis and disease progression by machine learning-driven biomarker search. Conclusions: Despite the limited sample size, this study pioneers in reporting time-series proteomic alterations in serum and CSF EVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.

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