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Brain, Jan 16 2024, awae017 | https://doi.org/10.1093/brain/awae017 Morc2a variants cause hydroxyl radical-mediated neuropathy and are rescued by restoring GHKL ATPase

Hye Yoon Chung ¹, Geon Seong Lee¹, Soo Hyun Nam ², Jeong Hyeon Lee ¹, Jeong Pil Han ¹, Sumin Song ¹, Gap-Don Kim ¹, Choonkyun Jung ¹, Do Young Hyeon ³, Daehee Hwang ^3,4, Byung-Ok Choi ^2,5,6, Su Cheong Yeom ^1,7

¹Graduate School of International Agricultural Technology and Institute of Green-Bio Science and Technology, Seoul National University, 1447, Pyeongchang, Kangwon 25354, Korea.

²Cell & Gene Therapy Institute, Samsung Medical Center, Seoul 06351, Korea.

³School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.

⁴Bioinformatics Institute, Bio-MAX, Seoul National University, Seoul 08826, Republic of Korea.

⁵Department of Health Science and Technology, Samsung Advanced Institute for Health Sciences & Technology, 81, Seoul 06351, Korea.

⁶Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Seoul 06351, Korea.

⁷WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Korea.

Hye Yoon Chung and Geon Seong Lee contributed equally to this work.

Correspondence may also be addressed to: Byung-Ok Choi

Correspondence to: Su Cheong Yeom

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 central nervous system 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 functional characteristics due to protein synthesis defects in Morc2a p.S87L was 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.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-01-17)
연구진국내 연구진
분야 생명과학 > 수의학

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