2. Academic Validation
  3. Impaired PARP1-dependent DNA repair in MORC2 mutations drives axonal degeneration in Charcot-Marie-Tooth disease subtype 2Z and spinal muscular atrophy-like neuromotor disorders

Impaired PARP1-dependent DNA repair in MORC2 mutations drives axonal degeneration in Charcot-Marie-Tooth disease subtype 2Z and spinal muscular atrophy-like neuromotor disorders

  • Pharmacol Res. 2026 Feb:224:108103. doi: 10.1016/j.phrs.2026.108103.
Mengli Wang 1,  Honglan Yang 2,  Zhongzheng Li 1,  Sen Zeng 1,  Ke Xu 1,  Binghao Wang 3,  Yongzhi Xie 4,  Qingping Wang 1,  Zhuolin Su 1,  Mingri Zhao 5,  Yiti Zhang 5,  Mujun Liu 6,  Beisha Tang 7,  Xionghao Liu 8,  Ruxu Zhang 9
Affiliations

Affiliations

  • 1 Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
  • 2 Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha 410013, China; Department of Neurology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
  • 3 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, China.
  • 4 Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
  • 5 Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410083, China.
  • 6 Department of Cell Biology, School of Life Sciences, Central South University, Changsha 410083, China.
  • 7 National Clinical Research Center for Geriatric Disorders, Central South University, Changsha 410008, China.
  • 8 Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410083, China. Electronic address: [email protected].
  • 9 Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha 410013, China. Electronic address: [email protected].
PMID: 41548771 DOI: 10.1016/j.phrs.2026.108103
Abstract

MORC2 mutations are associated with a spectrum of neuromotor disorders, including Charcot-Marie-Tooth disease subtype 2Z (CMT2Z) and a spinal muscular atrophy (SMA)-like phenotype. However, the mechanisms underlying these conditions remain unclear. In this study, we used iPSC-derived motor neurons (iPSC-MNs) carrying three distinct MORC2 mutations, p.S87L (SMA-like), p.Q400R, and p.D466N (CMT2Z), to examine their effects on cellular processes. Our results show that MORC2 mutations induce Apoptosis, DNA damage, and axonal pathology, including shortened neurites, elevated axonal breakage, and increased axonal swellings, with the most severe phenotypes observed in iPSC-MNs harboring p.S87L. Mechanistically, these mutations impair DNA repair by disrupting the interaction between MORC2 and PARP1, leading to reduced PARP1 activity and expression, as well as diminished DNA repair protein expression and recruitment. Notably, inhibition of PAR degradation with PDD restored PAR levels, reduced DNA damage accumulation, and ameliorated axonal pathology in p.S87L-mutant iPSC-MNs. These findings demonstrate that MORC2 mutations impair DNA repair through PARP1-dependent pathways, contributing to axonal degeneration. Targeting the PAR signaling pathway with inhibitors such as PDD may therefore represent a promising therapeutic avenue for MORC2-related neuromotor disorders.

Keywords

Charcot-Marie-Tooth disease type 2Z; DNA repair; IPSC-MNs; Microrchidia family CW-type zinc finger 2 gene; PARP1 and PAR; Spinal muscular atrophy-like.

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