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.

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.