한빛사논문
- 조회674
경희대학교 의과대학
Dallah Yoo, MD,1 Wonjae Lee, MS,2,3 Seung-Jae Lee, PhD,2 Jung-Joon Sung, MD, PhD,4 Gye Sun Jeon, PhD,4,5 Jae-Jun Ban, PhD,4,5 Chaewon Shin, MD, PhD,6 Jungho Kim, PhD,7 Hyo Sun Kim, PhD,7 and Tae-Beom Ahn, MD, PhD1*
1Department of Neurology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Republic of Korea 2Department of Biomedical Sciences, Neuroscience Research Institute, and Department of Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea 3Neuramedy Co., Ltd, Seoul, Republic of Korea 4Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea 5Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea 6Department of Neurology, Neuroscience Center, Chungnam National University Sejong Hospital, Chungnam National University College of Medicine, Sejong-si, Republic of Korea 7Laboratory of Molecular and Cellular Biology, Department of Life Science, Sogang University, Seoul, Republic of Korea
*Correspondence to: Professor Tae-Beom Ahn
Abstract
Background
Tropomyosin-receptor kinase fused gene (TFG) functions as a regulator of intracellular protein packaging and trafficking at the endoplasmic reticulum exit sites. TFG has recently been proposed as a cause of multisystem proteinopathy.
Objectives
Here, we describe a Korean family presenting with Parkinson's disease or amyotrophic lateral sclerosis caused by a novel variant of TFG (c.1148 G > A, p.Arg383His).
Methods
We collected clinical, genetic, dopamine transporter imaging, nerve conduction, and electromyography data from the seven subjects. To verify the pathogenicity of the R383H variant, we studied cell viability and the abnormal aggregation of α-synuclein and TAR DNA-binding protein 43 (TDP-43) in HeLa cells expressing R383H-TFG.
Results
The clinical phenotypes of the R383H-TFG mutation varied; of the five family members, one had Parkinson's disease, three had subclinical parkinsonism, and one (the proband) had amyotrophic lateral sclerosis. The individual with multiple system atrophy was the proband's paternal cousin, but the TFG genotype was not confirmed due to unavailability of samples. Our in vitro studies showed that R383H-TFG overexpression impaired cell viability. In cells co-expressing R383H-TFG and α-synuclein, insoluble α-synuclein aggregates increased in concentration and were secreted from the cells and co-localized with R383H-TFG. The levels of cytoplasmic insoluble aggregates of TDP-43 increased in HeLa cells expressing R383H-TFG and co-localized with R383H-TFG.
Conclusions
Clinical and in vitro studies have supported the pathogenic role of the novel TFG mutation in α-synucleinopathy and TDP-43 proteinopathy. These findings expand the phenotypic spectrum of TFG and suggest a pivotal role of endoplasmic reticulum dysfunction during neurodegeneration. © 2021 International Parkinson and Movement Disorder Society
논문정보
- Research article
- 2021년 11월 (BRIC 등록일 2021-11-23)
- 국내 연구진
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