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Morc2a variants cause hydroxyl radical-mediated neuropathy and are rescued by restoring GHKL ATPase.
Chung, Hye Yoon; Lee, Geon Seong; Nam, Soo Hyun; Lee, Jeong Hyeon; Han, Jeong Pil; Song, Sumin; Kim, Gap-Don; Jung, Choonkyun; Hyeon, Do Young; Hwang, Daehee; Choi, Byung-Ok; Yeom, Su Cheong.
Afiliação
  • Chung HY; Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology, Seoul National University, Kangwon 25354, Korea.
  • Lee GS; Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology, Seoul National University, Kangwon 25354, Korea.
  • Nam SH; Samsung Medical Center, Cell & Gene Therapy Institute, Seoul 06351, Korea.
  • Lee JH; Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology, Seoul National University, Kangwon 25354, Korea.
  • Han JP; Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology, Seoul National University, Kangwon 25354, Korea.
  • Song S; Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology, Seoul National University, Kangwon 25354, Korea.
  • Kim GD; Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology, Seoul National University, Kangwon 25354, Korea.
  • Jung C; Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology, Seoul National University, Kangwon 25354, Korea.
  • Hyeon DY; School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.
  • Hwang D; School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.
  • Choi BO; Bioinformatics Institute, Bio-MAX, Seoul National University, Seoul 08826, Republic of Korea.
  • Yeom SC; Samsung Medical Center, Cell & Gene Therapy Institute, Seoul 06351, Korea.
Brain ; 147(6): 2114-2127, 2024 Jun 03.
Article em En | MEDLINE | ID: mdl-38227798
ABSTRACT
Mutations in the Microrchidia CW-type zinc finger 2 (MORC2) GHKL ATPase module cause a broad range of neuropathies, such as Charcot-Marie-Tooth disease type 2Z; however, the aetiology and therapeutic strategy are not fully understood. Previously, we reported that the Morc2a p.S87L mouse model exhibited neuropathy and muscular dysfunction through DNA damage accumulation. In the present study, we analysed the gene expression of Morc2a p.S87L mice and designated the primary causing factor. We investigated the pathological pathway using Morc2a p.S87L mouse embryonic fibroblasts and human fibroblasts harbouring MORC2 p.R252W. We subsequently assessed the therapeutic effect of gene therapy administered to Morc2a p.S87L mice. This study revealed that Morc2a p.S87L causes a protein synthesis defect, resulting in the loss of function of Morc2a and high cellular apoptosis induced by high hydroxyl radical levels. We considered the Morc2a GHKL ATPase domain as a therapeutic target because it simultaneously complements hydroxyl radical scavenging and ATPase activity. We used the adeno-associated virus (AAV)-PHP.eB serotype, which has a high CNS transduction efficiency, to express Morc2a or Morc2a GHKL ATPase domain protein in vivo. Notably, AAV gene therapy ameliorated neuropathy and muscular dysfunction with a single treatment. Loss-of-function characteristics due to protein synthesis defects in Morc2a p.S87L were also noted in human MORC2 p.S87L or p.R252W variants, indicating the correlation between mouse and human pathogenesis. In summary, CMT2Z is known as an incurable genetic disorder, but the present study demonstrated its mechanisms and treatments based on established animal models. This study demonstrates that the Morc2a p.S87L variant causes hydroxyl radical-mediated neuropathy, which can be rescued through AAV-based gene therapy.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Terapia Genética Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Brain Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Terapia Genética Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Brain Ano de publicação: 2024 Tipo de documento: Article