2024/09/24
Keio University
A research group including Professor Hideyuki Okano (Center Director, Keio University Regenerative Medicine Research Center (KRM); at the time of research: Professor, Department of Physiology, Keio University School of Medicine), Project Professor Daisuke Ito (Department of Neurology, Keio University School of Medicine; at the time of research: Project Professor, Department of Physiology, Keio University School of Medicine), and Assistant Professor Kensuke Okada (Department of Neurology, Keio University School of Medicine) has successfully created a novel mouse model of amyotrophic lateral sclerosis (ALS) using the CRISPR-Cas9 genome-editing system. A point mutation corresponding to theFUS(fused-in sarcoma) gene abnormality (FUS-H517D), the second most common cause of familial ALS in Japan after abnormalities in theSOD1gene, was introduced into this model mouse. Unlike conventional transgenic mice, this newly created mouse model, which has a genetic mutation added to the endogenousFUSgene using genome-editing technology, can be used under more physiological conditions as a disease model closer to patients for pathophysiological analysis and therapeutic drug development. With aging, this model mouse exhibited motor dysfunctions such as walking difficulties, and in addition to a decrease in spinal motor neurons, it showed defects in the nuclear envelope and nuclear pore complexes, as well as DNA damage. Furthermore, we identified defects in the nuclear envelope and nuclear pore complexes in motor neurons differentiated from iPS cells derived from an ALS patient with the same mutation (FUS-H517D) that we established. RNA-seq analysis revealed that many genes related to the nuclear envelope and nuclear pore complexes were significantly downregulated in motor neurons with theFUS-H517D mutation. Additionally, defects in the nuclear envelope and nuclear pore complexes of spinal motor neurons were also demonstrated in post-mortem tissues from ALS patients.
Defects in the nuclear envelope, which is essential for nerve cells, are a critical factor in maintaining cell survival. Without correcting these nuclear envelope defects, a cure for ALS cannot be expected. These research findings demonstrate that genome-edited mice replicating the genetic abnormalities seen in ALS exhibit age-dependent motor dysfunction, and that defects in the nuclear envelope and nuclear pore complexes in spinal motor neurons represent a definitive pathogenic mechanism and a novel therapeutic target for ALS. By combining research materials such as genome-edited mice, iPS cells, and patient pathological samples, our understanding of ALS pathology will be deepened, and the development of therapeutic drugs will be significantly advanced.
This research was published in the international academic journalBrain, issued by Oxford University Press, on September 24, 2024, at 5:00 a.m. (Pacific Standard Time).
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