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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  kyouindb  KAKEN_id
Takenouchi, Toshiki
Hijikata, Atsushi
Shirai, Tsuyoshi
Suzuki, Hisato
Kosaki, Kenjiro
Saito, Megumu K
Takita, Junko  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0002-2452-6520 (unconfirmed)
Yoshida, Takeshi  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0003-0992-064X (unconfirmed)
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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