Multiple lines of evidence for disruption of nuclear lamina and nucleoporins in FUS amyotrophic lateral sclerosis.

Autor:	Okada K; Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan.; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.; Keio University iPS Cell Research Center for Intractable Neurological Diseases (KiND), Keio University Global Research Institute, Tokyo 108-0073, Japan., Ito D; Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan.; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.; Keio University iPS Cell Research Center for Intractable Neurological Diseases (KiND), Keio University Global Research Institute, Tokyo 108-0073, Japan.; Memory Center, Keio University School of Medicine, Tokyo 160-8582, Japan., Morimoto S; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.; Keio University iPS Cell Research Center for Intractable Neurological Diseases (KiND), Keio University Global Research Institute, Tokyo 108-0073, Japan.; Keio University Regenerative Medicine Research Center, Kanagawa, 210-0821, Japan.; Division of Neurodegenerative Disease Research, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, 173-0015, Japan., Kato C; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.; Keio University Regenerative Medicine Research Center, Kanagawa, 210-0821, Japan.; Division of Neurodegenerative Disease Research, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, 173-0015, Japan., Oguma Y; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.; Keio University Regenerative Medicine Research Center, Kanagawa, 210-0821, Japan., Warita H; Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan., Suzuki N; Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan., Aoki M; Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan., Kuramoto J; Department of Pathology, Keio University School of Medicine, Tokyo, 160-8582, Japan., Kobayashi R; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan., Shinozaki M; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.; Keio University Regenerative Medicine Research Center, Kanagawa, 210-0821, Japan., Ikawa M; Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan., Nakahara J; Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan.; Keio University iPS Cell Research Center for Intractable Neurological Diseases (KiND), Keio University Global Research Institute, Tokyo 108-0073, Japan., Takahashi S; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.; Keio University iPS Cell Research Center for Intractable Neurological Diseases (KiND), Keio University Global Research Institute, Tokyo 108-0073, Japan.; Keio University Regenerative Medicine Research Center, Kanagawa, 210-0821, Japan.; Department of Neurology and Stroke, Saitama Medical University International Medical Center, Saitama, 350-1298, Japan., Nishimoto Y; Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan., Shibata S; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.; Division of Microscopic Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, 951-8510, Japan., Okano H; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.; Keio University iPS Cell Research Center for Intractable Neurological Diseases (KiND), Keio University Global Research Institute, Tokyo 108-0073, Japan.; Keio University Regenerative Medicine Research Center, Kanagawa, 210-0821, Japan.; Division of Neurodegenerative Disease Research, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, 173-0015, Japan.; Laboratory for Marmoset Models of Neural Diseases, RIKEN Center for Brain Science, Saitama, 351-0198, Japan.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2024 Nov 04; Vol. 147 (11), pp. 3933-3948.
DOI:	10.1093/brain/awae224
Abstrakt:	Advanced pathological and genetic approaches have revealed that mutations in fused in sarcoma/translated in liposarcoma (FUS/TLS), which is pivotal for DNA repair, alternative splicing, translation and RNA transport, cause familial amyotrophic lateral sclerosis (ALS). The generation of suitable animal models for ALS is essential for understanding its pathogenesis and developing therapies. Therefore, we used CRISPR-Cas9 to generate FUS-ALS mutation in the non-classical nuclear localization signal (NLS), H517D (mouse position: H509D) and genome-edited mice. Fus WT/H509D mice showed progressive motor impairment (accelerating rotarod and DigiGait system) with age, which was associated with the loss of motor neurons and disruption of the nuclear lamina and nucleoporins and DNA damage in spinal cord motor neurons. We confirmed the validity of our model by showing that nuclear lamina and nucleoporin disruption were observed in lower motor neurons differentiated from patient-derived human induced pluripotent stem cells (hiPSC-LMNs) with FUS-H517D and in the post-mortem spinal cord of patients with ALS. RNA sequence analysis revealed that most nuclear lamina and nucleoporin-linking genes were significantly decreased in FUS-H517D hiPSC-LMNs. This evidence suggests that disruption of the nuclear lamina and nucleoporins is crucial for ALS pathomechanisms. Combined with patient-derived hiPSC-LMNs and autopsy samples, this mouse model might provide a more reliable understanding of ALS pathogenesis and might aid in the development of therapeutic strategies. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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