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TGF beta 4 alleviates the phenotype of Charcot-Marie-Tooth disease type 1A

Authors
Jeon, HyeonjinJang, So YoungKwak, GeonYi, Yong WeonYou, Mi-HyeonPark, Na YoungJo, Ju HeeYang, Ji WonJang, Hye JiJeong, Sun-YoungMoon, Seung KeeDoo, Hyun MyungNahm, MinyeopKim, DonghoonChang, Jong WookChoi, Byung-OkHong, Young Bin
Issue Date
May-2023
Publisher
Oxford University Press
Keywords
Charcot-Marie-Tooth disease (CMT); peripheral myelin protein 22 (PMP22); demyelination; Nodal; transforming growth factor beta 4 (TGF beta 4)
Citation
Brain
Journal Title
Brain
URI
http://scholarworks.bwise.kr/kbri/handle/2023.sw.kbri/127
DOI
10.1093/brain/awad147
ISSN
0006-8950
Abstract
The duplication of the peripheral myelin protein 22 (PMP22) gene causes a demyelinating type of neuropathy, commonly known as Charcot-Marie-Tooth disease type 1A (CMT1A). Development of effective drugs for CMT1A still remains as an unmet medical need. In the present study, we assessed the role of the transforming growth factor beta 4 (TGF beta 4)/Nodal axis in the pathogenesis of CMT1A. First, we identified PMP22 overexpression-induced Nodal expression in Schwann cells, which might be one of the downstream effectors in CMT1A. Administration of Nodal protein at the developmental stage of peripheral nerves induced the demyelinating phenotype in vivo. Second, we further isolated TGF beta 4 as an antagonist that could abolish Nodal-induced demyelination. Finally, we developed a recombinant TGF beta 4-fragment crystallizable (Fc) fusion protein, CX201, and demonstrated that its application had promyelinating efficacy in Schwann cells. CX201 administration improved the demyelinating phenotypes of CMT1A mouse models at both pre-symptomatic and post-symptomatic stages. These results suggest that the TGF beta 4/Nodal axis plays a crucial role in the pathogenesis of CMT1A and might be a potential therapeutic target for CMT1A.
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