Article (Scientific journals)
Novel lissencephaly-associated NDEL1 variant reveals distinct roles of NDE1 and NDEL1 in nucleokinesis and human cortical malformations
Tsai, M.-H.; Ke, H.-C.; Lin, W.-C. et al.
2024In Acta Neuropathologica, 147 (1)
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Keywords :
DYNC1H1; Dynein; Interkinetic nuclear migration; LIS1; Lissencephaly; Microcephaly; Microlissencephaly; NDE1; NDEL1; Neuronal migration; Nucleokinesis; PAFAH1B1; Radial glial cell; Carrier Proteins; Cell Movement; Cell Proliferation; Cerebral Cortex; Dyneins; Humans; Microtubule-Associated Proteins; anticonvulsive agent; arginine; dynein adenosine triphosphatase; glutamine; peptides and proteins; protein NDE1; protein NDEL1; tryptophan; unclassified drug; carrier protein; microtubule associated protein; Nde1 protein, human; NDEL1 protein, human; absence seizure; animal cell; animal experiment; animal model; animal tissue; anticonvulsant therapy; Article; atonic seizure; brain cortex; brain development; case report; cell differentiation; cell migration; cell motion; cell nucleus; centrosome; child; clinical article; controlled study; corpus callosum; developmental delay; electroporation; embryo; female; gene expression; gene knockdown; genetic variability; human; infantile hypotonia; infantile spasm; intellectual impairment; language delay; language disability; macrogyria; male; mouse; myoclonus seizure; nerve cell culture; neural stem cell; neuroimaging; nonhuman; nuclear magnetic resonance imaging; nucleokinesis; preschool child; protein binding; psychomotor disorder; Sanger sequencing; school child; single cell RNA seq; somatic mutation; subcortical heterotopia; tonic clonic seizure; transcriptomics; agyria; cell proliferation; genetics
Abstract :
[en] The development of the cerebral cortex involves a series of dynamic events, including cell proliferation and migration, which rely on the motor protein dynein and its regulators NDE1 and NDEL1. While the loss of function in NDE1 leads to microcephaly-related malformations of cortical development (MCDs), NDEL1 variants have not been detected in MCD patients. Here, we identified two patients with pachygyria, with or without subcortical band heterotopia (SBH), carrying the same de novo somatic mosaic NDEL1 variant, p.Arg105Pro (p.R105P). Through single-cell RNA sequencing and spatial transcriptomic analysis, we observed complementary expression of Nde1/NDE1 and Ndel1/NDEL1 in neural progenitors and post-mitotic neurons, respectively. Ndel1 knockdown by in utero electroporation resulted in impaired neuronal migration, a phenotype that could not be rescued by p.R105P. Remarkably, p.R105P expression alone strongly disrupted neuronal migration, increased the length of the leading process, and impaired nucleus–centrosome coupling, suggesting a failure in nucleokinesis. Mechanistically, p.R105P disrupted NDEL1 binding to the dynein regulator LIS1. This study identifies the first lissencephaly-associated NDEL1 variant and sheds light on the distinct roles of NDE1 and NDEL1 in nucleokinesis and MCD pathogenesis. © 2024, The Author(s).
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Tsai, M.-H.;  Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
Ke, H.-C.;  School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
Lin, W.-C.;  Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
Nian, Fang-Shin ;  Université de Liège - ULiège > GIGA > GIGA Neurosciences - Molecular Regulation of Neurogenesis ; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
Huang, C.-W.;  Faculty of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
Cheng, Haw-Yuan  ;  Université de Liège - ULiège > GIGA > GIGA Neurosciences - Molecular Regulation of Neurogenesis ; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
Hsu, C.-S.;  Advanced Therapeutics Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
Granata, T.;  Genomics Center for Clinical and Biotechnological Applications, Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
Chang, C.-H.;  Department of Paediatric Neuroscience, European Reference Network EPIcare, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Castellotti, B.;  Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Lin, S.-Y.;  Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
Doniselli, F.M.;  Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Lu, C.-J.;  Integrated Diagnostics for Epilepsy, Department of Diagnostic and Technology, European Reference Network EPIcare, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Franceschetti, S.;  Institute of Anatomy and Cell Biology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
Ragona, F.;  Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
Hou, P.-S.;  Institute of Biochemistry and Molecule Biology, College of Life Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
Canafoglia, L.;  Department of Biological Science and Technology, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
Tung, C.-Y.
Lee, M.-H.
Wang, W.-J.
Tsai, J.-W.
More authors (11 more) Less
Language :
English
Title :
Novel lissencephaly-associated NDEL1 variant reveals distinct roles of NDE1 and NDEL1 in nucleokinesis and human cortical malformations
Publication date :
2024
Journal title :
Acta Neuropathologica
ISSN :
0001-6322
eISSN :
1432-0533
Publisher :
Springer Science and Business Media Deutschland GmbH
Volume :
147
Issue :
1
Peer reviewed :
Peer Reviewed verified by ORBi
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