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ID 110142
Title Alternative
近位筋優位運動感覚ニューロパチー(HMSN-P)患者iPS細胞から分化した神経細胞はプロテアソーム障害を認める
Author
Murakami, Nagahisa Tokushima University|Kyoto University
Imamura, Keiko Kyoto University
Egawa, Naohiro Kyoto University
Tsukita, Kayoko Kyoto University
Enami, Takako Kyoto University
Yamamoto, Takuya Kyoto University
Inoue, Haruhisa Kyoto University
Keywords
HMSN-P
TFG
UPS
iPSCs
Gene correction
CRISPR-Cas9
Neurodegeneration
Content Type
Thesis or Dissertation
Description
Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is caused by a heterozygous mutation (P285L) in Tropomyosin-receptor kinase Fused Gene (TFG), histopathologically characterized by progressive spinal motor neuron loss with TFG cytosolic aggregates. Although the TFG protein, found as a type of fusion oncoprotein, is known to facilitate vesicle transport from endoplasmic reticulum (ER) to Golgi apparatus at ER exit site, it is unclear how mutant TFG causes motor neuron degeneration. Here we generated induced pluripotent stem cells (iPSCs) from HMSN-P patients, and differentiated the iPSCs into neural cells with spinal motor neurons (iPS-MNs). We found that HMSN-P patient iPS-MNs exhibited ubiquitin proteasome system (UPS) impairment, and HMSN-P patient iPS-MNs were vulnerable to UPS inhibitory stress. Gene correction of the mutation in TFG using the CRISPR-Cas9 system reverted the cellular phenotypes of HMSN-P patient iPS-MNs. Collectively, these results suggest that our cellular model with defects in cellular integrity including UPS impairments may lead to identification of pathomechanisms and a therapeutic target for HMSN-P.
Journal Title
Molecular Brain
ISSN
17566606
Publisher
Springer nature
Volume
10
Start Page
7
Published Date
2017-02-15
Remark
内容要旨・審査要旨・論文本文の公開:
内容要旨・審査要旨:LID201705291003.pdf
論文本文:LID201705291004.pdf
本論文は, 著者Nagahisa Murakamiの学位論文として提出され, 学位審査・授与の対象となっている。
Rights
Copyright:©The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3094号
Diploma Number
甲医第1338号
Granted Date
2017-04-27
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
University Hospital
Medical Sciences