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タイトル: | Involvement of mTOR pathway in neurodegeneration in NSF-related developmental and epileptic encephalopathy |
著者: | Hayashi, Takahiro Yano, Naoko Kora, Kengo Yokoyama, Atsushi Maizuru, Kanako Kayaki, Taisei Nishikawa, Kinuko Osawa, Mitsujiro Niwa, Akira ![]() ![]() Takenouchi, Toshiki Hijikata, Atsushi Shirai, Tsuyoshi Suzuki, Hisato Kosaki, Kenjiro Saito, Megumu K Takita, Junko ![]() ![]() ![]() Yoshida, Takeshi ![]() ![]() ![]() |
著者名の別形: | 林, 貴大 矢野, 直子 甲良, 謙伍 横山, 淳史 舞鶴, 賀奈子 栢木, 大誓 西川, 絹子 大澤, 光次郎 丹羽, 明 齋藤, 潤 滝田, 順子 吉田, 健司 |
キーワード: | autophagy neurites pc12 cells nephrogenic fibrosing dermopathy mtor serine-threonine kinases tissue degeneration encephalopathic epilepsy |
発行日: | 15-May-2023 |
出版者: | Oxford University Press (OUP) |
誌名: | Human Molecular Genetics |
巻: | 32 |
号: | 10 |
開始ページ: | 1683 |
終了ページ: | 1697 |
抄録: | Membrane fusion is mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. During neurotransmitter exocytosis, SNARE proteins on a synaptic vesicle and the target membrane form a complex, resulting in neurotransmitter release. N-ethylmaleimide-sensitive factor (NSF), a homohexameric ATPase, disassembles the complex, allowing individual SNARE proteins to be recycled. Recently, the association between pathogenic NSF variants and developmental and epileptic encephalopathy (DEE) was reported; however, the molecular pathomechanism of NSF-related DEE remains unclear. Here, three patients with de novo heterozygous NSF variants were presented, of which two were associated with DEE and one with a very mild phenotype. One of the DEE patients also had hypocalcemia from parathyroid hormone deficiency and neuromuscular junction impairment. Using PC12 cells, a neurosecretion model, we show that NSF with DEE-associated variants impaired the recycling of vesicular membrane proteins and vesicle enlargement in response to exocytotic stimulation. In addition, DEE-associated variants caused neurodegenerative change and defective autophagy through overactivation of the mTOR pathway. Treatment with rapamycin, an mTOR inhibitor, or overexpression of wild-type NSF ameliorated these phenotypes. Furthermore, neurons differentiated from patient-derived induced pluripotent stem cells showed neurite degeneration, which was also alleviated by rapamycin treatment or gene correction using genome editing. Protein structure analysis of NSF revealed that DEE-associated variants might disrupt the transmission of the conformational change of NSF monomers and consequently halt the rotation of ATP hydrolysis, indicating a dominant negative mechanism. In conclusion, this study elucidates the pathomechanism underlying NSF-related DEE and identifies a potential therapeutic approach. |
著作権等: | © The Author(s) 2023. Published by Oxford University Press. All rights reserved. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
URI: | http://hdl.handle.net/2433/286807 |
DOI(出版社版): | 10.1093/hmg/ddad008 |
PubMed ID: | 36645181 |
出現コレクション: | 学術雑誌掲載論文等 |

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