Neural Regeneration Research ›› 2024, Vol. 19 ›› Issue (1): 205-211.doi: 10.4103/1673-5374.375347

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The MORC2 p.S87L mutation reduces proliferation of pluripotent stem cells derived from a patient with the spinal muscular atrophy-like phenotype by inhibiting proliferation-related signaling pathways

Sen Zeng1, #, Honglan Yang1, #, Binghao Wang2, Yongzhi Xie3, Ke Xu1, Lei Liu1, 4, Wanqian Cao1, Xionghao Liu5, Beisha Tang6, Mujun Liu7, *, Ruxu Zhang1, *#br#   

  1. 1Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China; 2Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; 3Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China; 4Health Management Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China; 5Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan Province, China; 6National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan Province, China; 7Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan Province, China
  • Online:2024-01-15 Published:2023-08-02
  • Contact: Ruxu Zhang, MD, PhD, zhangruxu@vip.163.com; Mujun Liu, PhD, liumujun03@csu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 82171172 (to RZ) and 81771366 (to RZ) and Fundamental Research Funds for the Central Universities of Central South University, Nos. 2021zzts1095 (to SZ) and 2022zzts0832 (to HY).

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Abstract:

Mutations in the microrchidia CW-type zinc finger protein 2 (MORC2) gene are the causative agent of Charcot-Marie-Tooth disease type 2Z (CMT2Z), and the hotspot mutation p.S87L is associated with a more severe spinal muscular atrophy-like clinical phenotype. The aims of this study were to determine the mechanism of the severe phenotype caused by the MORC2 p.S87L mutation and to explore potential treatment strategies. Epithelial cells were isolated from urine samples from a spinal muscular atrophy (SMA)-like patient (MORC2 p.S87L), a CMT2Z patient (MORC2 p.Q400R), and a healthy control and induced to generate pluripotent stem cells, which were then differentiated into motor neuron precursor cells. Next-generation RNA sequencing followed by KEGG pathway enrichment analysis revealed that differentially expressed genes involved in the PI3K/Akt and MAPK/ERK signaling pathways were enriched in the p.S87L SMA-like patient group and were significantly downregulated in induced pluripotent stem cells. Reduced proliferation was observed in the induced pluripotent stem cells and motor neuron precursor cells derived from the p.S87L SMA-like patient group compared with the CMT2Z patient group and the healthy control. G0/G1 phase cell cycle arrest was observed in induced pluripotent stem cells derived from the p.S87L SMA-like patient. MORC2 p.S87L-specific antisense oligonucleotides (p.S87L-ASO-targeting) showed significant efficacy in improving cell proliferation and activating the PI3K/Akt and MAPK/ERK pathways in induced pluripotent stem cells. However, p.S87L-ASO-targeting did not rescue proliferation of motor neuron precursor cells. These findings suggest that downregulation of the PI3K/Akt and MAPK/ERK signaling pathways leading to reduced cell proliferation and G0/G1 phase cell cycle arrest in induced pluripotent stem cells might be the underlying mechanism of the severe p.S87L SMA-like phenotype. p.S87L-ASO-targeting treatment can alleviate disordered cell proliferation in the early stage of pluripotent stem cell induction. 

Key words: antisense oligonucleotides, cell cycle arrest, Charcot-Marie-Tooth disease 2Z, induced pluripotent stem cells, MAPK/ERK, PI3K/Akt, proliferation, spinal muscular atrophy-like