TGFβ4 alleviates the phenotype of Charcot-Marie-Tooth disease type 1A.

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 (TGFβ4)/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 TGFβ4 as an antagonist that could abolish Nodal-induced demyelination. Finally, we developed a recombinant TGFβ4-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 TGFβ4/Nodal axis plays a crucial role in the pathogenesis of CMT1A and might be a potential therapeutic target for CMT1A.

• Authors: Hyeonjin Jeon, So Young Jang, Geon Kwak, Yong Weon Yi, Mi-Hyeon You, Na Young Park, Ju Hee Jo, Ji Won Yang, Hye Ji Jang, Sun-Young Jeong, Seung Kee Moon, Hyun Myung Doo, Minyeop Nahm, Donghoon Kim, Jong Wook Chang, Byung-Ok Choi, Young Bin Hong
• Journal: Brain : a journal of neurology (Brain) Vol. 146 Issue 9 Pg. 3608-3615 (09 01 2023) ISSN: 1460-2156 [Electronic] England
• PMID: 37143322 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Myelin Proteins
• Transforming Growth Factor beta

Topics

• Animals
• Mice
• Charcot-Marie-Tooth Disease (pathology)
• Myelin Proteins (metabolism)
• Schwann Cells
• Phenotype
• Transforming Growth Factor beta (metabolism)