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Protein profiling of extracellular vesicles from iPSC-derived astrocytes of patients with ALS/PDC in Kii peninsula

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Abstract

Background

Amyotrophic lateral sclerosis/Parkinsonism-dementia complex in Kii peninsula, Japan (Kii ALS/PDC), is an endemic neurodegenerative disease whose causes and pathogenesis remain unknown. However, astrocytes in autopsied cases of Kii ALS/PDC show characteristic lesions. In addition, relationships between extracellular vesicles (EVs) and neurodegenerative diseases are increasingly apparent. Therefore, we focused on proteins in EVs derived from Kii ALS/PDC astrocytes in the present study.

Methods

Induced pluripotent stem cells (iPSCs) derived from three healthy controls (HCs) and three patients with Kii ALS/PDC were differentiated into astrocytes. EVs in the culture medium of astrocytes were collected and subjected to quantitative proteome analysis.

Results

Our proteome analysis reveals that EV-containing proteins derived from astrocytes of patients with Kii ALS/PDC show distinctive patterns compared with those of HCs. Moreover, EVs derived from Kii ALS/PDC astrocytes display increased proteins related to proteostasis and decreased proteins related to anti-inflammation.

Discussion

Proteins contained in EVs from astrocytes unveil protective support to neurons and may reflect the molecular pathomechanism of Kii ALS/PDC; accordingly, they may be potential biomarker candidates of Kii ALS/PDC.

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Fig. 1
Fig. 2

Data availability

The authors confirm that the data supporting the findings of this study are available within the article.

Abbreviations

Kii ALS/PDC :

Amyotrophic lateral sclerosis/Parkinsonism-dementia complex in Kii peninsula

ALS :

Amyotrophic lateral sclerosis

AD :

Alzheimer’s disease

PD :

Parkinson’s disease

EV:

Extracellular vesicle

HC :

Healthy control

iPSC :

Induced pluripotent stem cell

iPast :

IPSC-derived astrocyte

CNS :

Central nervous system

DAVID :

Database for annotation, visualization, and integrated discovery

KEGG :

Kyoto encyclopedia of genes and genomes

GO :

Gene ontology

PCA :

Principal component analysis

DAP :

Differentially abundant protein

CAND1 :

Cullin-associated NEDD8-disscoated protein

UPS :

Ubiquitin-proteasome system

DOLK :

Dolichol kinase

TAGLN3 :

Transgelin 3

APOE4 :

Apolipoprotein E4

NF-κB :

Nuclear factor κB

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Acknowledgements

We would like to express our thanks to the following laboratory member in the department of physiology, Keio University School of Medicine: Mr. Chris Kato and Mr. Naoki Kobayashi for their technical support related to data analysis and figure arrangement. We also thank Profs. Shinya Yamanaka and Masato Nakagawa, CiRA, Kyoto University for providing iPSCs (201B7 and 1201C1). We acknowledge his great contribution of Professor Shigeki Kuzuhara (1944-2021) to the study of Kii ALS/PDC. We thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

S.M. reports grant supports from Japan Society for the Promotion of Science (JSPS) (KAKENHI Grant No.JP15J03921, JP18K07368, JP18KK0239, JP19K17002, JP19K08002, JP21H05278, JP22K07500, and JP22K15736), the Japan Agency for Medical Research and Development (AMED) (Grant No. JP23bm1123046, JP23kk0305024), Japan Intractable Diseases Research Foundation, The Kanae Foundation for the Promotion of Medical Science, The Uehara Memorial Foundation, THE YUKIHIKO MIYATA MEMORIAL TRUST FOR ALS RESEARCH, Okasan-Kato Foundation Research Grant and Yoshio Koide Grant, Japan ALS Association during the conduct of the study. Y.K. reports grant supports from the Mie Medical Fund, Japan Foundation for Neuroscience and Mental Health, the Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases (H29-Nanchi-Ippan-085, collaborator, 2020–2022), the Research Committee of Muro Disease (Kii ALS/PDC) (Grant No. 21210301, Chair, 2009–2014), by the Ministry of Health, Labour and Welfare (MHLW), Japan, JSPS (KAKENHI Grant No. JP25305030, JP15K09364, JP17H01689, JP18K07514, JP18KK0239, and JP18K07368), and by a grant-in-aid of the Research Consortium of Kii ALS/PDC from AMED (Grant No. JP17ek0109139). H.O. reports grant supports from JSPS (KAKENHI Grant No. JP20H00485, JP21F21410, JP21H05273, and JP22KF0333) and AMED (Grant No. JP22bm0804003, JP20ek0109395, JP20ek0109329, JP21wm0425009, and JP23bm1423002).

Author information

Authors and Affiliations

  1. Department of Physiology, Keio University School of Medicine, Tokyo, Japan

    Hiroya Kobayashi, Satoru Morimoto, Mitsuru Ishikawa, Nicolas Leventoux & Hideyuki Okano

  2. Cancer Precision Medicine Center, Japanese Foundation of Cancer Research, Tokyo, Japan

    Koji Ueda

  3. Department of Oncologic Pathology, Mie University Graduate School of Medicine, Mie, Japan

    Satoru Morimoto & Yoshifumi Hirokawa

  4. School of Nursing, Suzuka University of Medical Science, Mie, Japan

    Ryogen Sasaki

  5. Kii ALS/PDC Research Center, Mie University Graduate School of Regional Innovation Studies, Mie, Japan

    Yasumasa Kokubo

Authors
  1. Hiroya Kobayashi
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  2. Koji Ueda
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  3. Satoru Morimoto
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  4. Mitsuru Ishikawa
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  5. Nicolas Leventoux
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  6. Ryogen Sasaki
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  7. Yoshifumi Hirokawa
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  8. Yasumasa Kokubo
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  9. Hideyuki Okano
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Contributions

The methodology was determined by H.K., K.U., and S.M. Experiment was carried out by K.U., S.M., M.I., and N.L. Data analysis was conducted by H.K. and K.U. A blood sample was collected by R.S., Y.H., and Y.K. The original manuscript was written by H.K. and reviewed and edited by K.U., S.M., M.I., N.L., R.S., Y.H., Y.K., and H.O. S.M. and H.O. supervised the project.

Corresponding authors

Correspondence to Satoru Morimoto or Hideyuki Okano.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the ethics committee of Mie University Hospital, (Approval no. 2561) and Keio University School of Medicine (Approval no. 20080016). Written informed consent was obtained from each patient or his/her family prior to this study.

Competing interests

H.O. reports grants and personal fees from K Pharma Inc. and SanBio Co. Ltd., apart from this submitted work.

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Cell lines

In this research, we used six cell lines as follows: HC1 = 201B7 (RRID: CVCL_A324), HC2 = WD39 (RRID: CVCL_Y528), HC3 = 1201C1 (RRID: CVCL_LJ37), Kii1 (D000509 RIKEN BRC: HPS1742), Kii2 (D000603 RIKEN BRC: HPS1780), and Kii3 (D000604 RIKEN BRC: HPS1781).

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Kobayashi, H., Ueda, K., Morimoto, S. et al. Protein profiling of extracellular vesicles from iPSC-derived astrocytes of patients with ALS/PDC in Kii peninsula. Neurol Sci 44, 4511–4516 (2023). https://doi.org/10.1007/s10072-023-07000-7

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  • DOI: https://doi.org/10.1007/s10072-023-07000-7

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