September 11, 2024
Keio University
A joint research group—including Director/Professor Hideyuki Okano (at the time of the research: Professor, Department of Physiology, Keio University School of Medicine) and Deputy Director/Project Associate Professor Satoru Morimoto (at the time of the research: Full-time Lecturer, Department of Physiology, Keio University School of Medicine) of the Keio University Regenerative Medicine Research Center (KRM); Kurizumi Kato, a fifth-year student at the Keio University School of Medicine; and Professor Yukinori Okada of the Department of Statistical Genetics, Osaka University Graduate School of Medicine (Team Leader, Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences; Professor, Department of Medical Genome Sciences, Graduate School of Medicine, The University of Tokyo)—conducted an integrated analysis. This analysis combined the pathogenic phenotypes and responsiveness to the candidate ALS treatment drug ropinirole hydrochloride (ropinirole) in lower motor neurons (LMNs) derived from induced pluripotent stem cells (iPSCs) of patients with sporadic amyotrophic lateral sclerosis (ALS) (iPSC-LMNs) with a polygenic risk score (PRS), a quantitative indicator of genetic background. The group discovered that total blood cholesterol is a genetic trait involved in the neurite length pathology and ropinirole responsiveness of iPSC-LMNs from patients with sporadic ALS.
The study found that the higher the PRS for total blood cholesterol—in other words, the stronger the genetic predisposition for high total blood cholesterol—the more fragile the neurites of iPSC-LMNs were, and the greater the improvement in neurites following ropinirole treatment. This finding is consistent with our previous research showing that ropinirole treatment suppresses the expression of cholesterol synthesis enzymes in iPSC-LMNs (Morimoto et al., *Cell Stem Cell*, 2023). Furthermore, an analysis using publicly available data revealed a high degree of consistency in the effect sizes of expression quantitative trait loci (eQTLs)—genetic variants that alter the gene expression of enzymes involved in cholesterol synthesis—between the liver, where 80% of total blood cholesterol is synthesized, and the spinal cord, where LMNs are located. Additionally, single-cell RNA sequencing (scRNA-seq) analysis of the lumbar spinal cord from healthy individuals suggested that LMNs have higher expression of genes for enzymes involved in cholesterol synthesis compared to other types of neurons and astrocytes, indicating active cholesterol synthesis.
In summary, we have discovered that in the LMNs of patients with sporadic ALS, physiologically active cholesterol synthesis is enhanced due to genetic predisposition, and that suppressing this enhancement may be one of the therapeutic mechanisms of ropinirole. These findings are considered important insights not only for understanding sporadic ALS but also for the development of therapeutic strategies. This research was published in the BMJ group's Journal of Neurology, Neurosurgery, and Psychiatry on September 4, 2024.
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