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Neurogenetics
Letter
Spinal cord motor neuron phenotypes and polygenic risk scores in sporadic amyotrophic lateral sclerosis: deciphering the disease pathology and therapeutic potential of ropinirole hydrochloride
  1. Chris Kato1,2,3,
  2. Satoru Morimoto1,2,3,
  3. Shinichi Takahashi1,2,4,
  4. Shinichi Namba5,6,7,
  5. Qingbo S Wang5,6,8,
  6. Yukinori Okada5,6,7,8,9,10,
  7. Hideyuki Okano1,2,3
  1. 1Keio University Regenerative Medicine Research Center (KRM), Kawasaki, Kanagawa, Japan
  2. 2Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
  3. 3Division of Neurodegenerative Disease Research, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Itabashi-ku, Tokyo, Japan
  4. 4Department of Neurology and Cerebrovascular Medicine, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan
  5. 5Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
  6. 6Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
  7. 7Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
  8. 8Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Osaka, Japan
  9. 9Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka, Japan
  10. 10Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka, Japan
  1. Correspondence to Professor Hideyuki Okano; hidokano{at}keio.jp; Dr Satoru Morimoto; satoru_morimoto{at}keio.jp

https://doi.org/10.1136/jnnp-2024-333690

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    Introduction

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by both upper and lower motor neuron (MN) degeneration. Approximately, 90% of patients with ALS have sporadic ALS (SALS). Thus, identifying the genetic factors of SALS is difficult. However, lower MNs (LMNs), including spinal MNs, that derive from induced pluripotent stem cells (iPSC-LMNs) in SALS patients exhibit ALS-like phenotypes,1 such as reduced neurite length (NL), suggesting a polygenic contribution to SALS pathogenesis.

    Drug screening using iPSC-LMNs recently identified ropinirole hydrochloride (ROPI) as a novel therapeutic candidate for ALS.1 A clinical trial of ROPI (the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial) involving 20 SALS patients suggested that ROPI inhibits the pathological progression in ALS development.2 Furthermore, our reverse translational study in the ROPALS trial revealed that patients who had iPSC-LMNs that responded strongly to ROPI showed greater clinical efficacy in the trial.2 This suggests that iPSC-LMN phenotypes reflect drug responsiveness in SALS patients.

    Recent Genome-Wide Association Studies (GWASs) have uncovered genetic predispositions for various traits in individuals. A recent GWAS in ALS patients suggested that the mutations associated with high levels of blood total cholesterol play a causal role in ALS development.3 The polygenic risk score (PRS) is a quantitative measure that is obtained by summing the small effects of each risk variant identified by GWASs and is widely used to predict diverse traits in individuals.

    In the present study, we aimed to identify the genetic factors in the development of SALS and the mechanism underlying the anti-ALS effect of ROPI by combining two indices that reflect genetic predisposition: the phenotype of iPSC-LMNs and the PRS (figure 1A).

    Figure 1

    Analysis of lower motor neuron derived from induced pluripotent stem cell (iPSC-LMN) phenotypes and polygenic risk scores (PRSs) in sporadic amyotrophic lateral sclerosis (SALS) patients …

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    Footnotes

    • X @NambaShinichi

    • Contributors CK, SM and ST designed the study and acquired samples from patients. CK analysed the data and performed statistical analyses. CK, SM, ST, SN, QW, YO and HO contributed to the interpretation of the results. ST, SN, QW, YO and HO provided supervision. CK and SM wrote the manuscript, and all authors corrected the manuscript and collectively made the decision to submit for publication.

    • Funding This study was supported by the grant support from Japan Society for the Promotion of Science (JSPS) (KAKENHI Grant No. JP21H05278 and JP22K15736 to SM, JP22K07500 to ST and JP20H00485 to HO), Japan Agency for Medical Research and Development (AMED) (Grant No. JP22ek0109616, JP23bm1123046, JP23kk0305024 to SM, JP21wm0425009, JP22bm0804003, JP22ek0109616, JP23bm1423002 to HO) and Miyata Yukihiko Memorial ALS Research Grant Foundation to SM, Yoshio Koide Grant, Japan ALS Association to SM, Daiichi Sankyo Foundation of Life Science to SM and UBE Academic Foundation to SM.

    • Competing interests HO reports grants and personal fees as a chief scientific officer from K Pharma during the conduct of the study; personal fees from Sanbio, outside the submitted work; In addition, HO has a patent on a therapeutic agent for amyotrophic lateral sclerosis and composition for treatment licensed to K Pharma. QW is currently an employee of Calico Life Science. Involvement in the presented research was prior to the affiliation. The other authors have declared that no conflict of interest exists.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.