2021/04/28
Keio University School of Medicine
Niigata University
A joint research team—including Dr. Masahiro Nogami of Takeda Pharmaceutical Company Limited; Professor Hideyuki Okano of the Department of Physiology, Keio University School of Medicine; Associate Professor Masato Yano of the Department of Neuroanatomy, Niigata University Graduate School of Medical and Dental Sciences; and Professor Masashi Aoki of the Department of Neurology, Tohoku University Graduate School of Medicine—has successfully discovered a group of hub genes that play a central role in the RNA expression network critical to its pathophysiology. This was achieved by analyzing familial amyotrophic lateral sclerosis (ALS) at the molecular level using a Bayesian network analysis method that leverages iPS cell-derived neurons and a supercomputer, named the iBRN method. The research was conducted as part of the Takeda Pharmaceutical Company Limited's Shonan Incubation Lab project, an industry-academia collaborative research initiative.
ALS is a neurodegenerative disease that selectively affects motor neurons, with primary symptoms of muscle atrophy and muscle weakness. It is a designated intractable disease with extremely rapid progression and few effective treatments. This research group conducted a Bayesian network analysis based on transcriptome information from 60 cell types, including various differentiation stages of iPS cell-derived motor neurons obtained from healthy individuals and patients with familial ALS carrying mutations in the FUS gene. Through this analysis, they identified three hub genes involved in the disease's pathophysiology: PRKDC, miR-125b-5p, and TIMELESS. Furthermore, using a cell model, they demonstrated that the activity of PRKDC is related to the abnormal localization of the FUS protein, a causative gene for ALS, and that the miR-125b-5p–TIMELESS molecular pathway causes DNA damage, a molecular pathogenic factor in neurodegeneration. In summary, the iBRN method established in this study not only demonstrates its effectiveness in exploring the molecular pathogenesis of neurodegenerative diseases but also suggests a new research strategy for elucidating the molecular pathogenesis of a wide range of diseases of unknown cause.
The results of this research were published in the online edition of "Neurobiology of Disease" on April 20, 2021 (U.S. Pacific Time).
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