C9ORF72-derived dipeptide repeat proteins have emerged as the pathogenic cause of neurodegener- ation in amyotrophic lateral sclerosis and frontotem- poral dementia (C9-ALS/FTD). However, the mecha- nisms underlying their expression are not fully un- derstood. Here, we demonstrate that ZNF598, the rate-limiting factor for ribosome-associated qual- ity control (RQC), co-translationally titrates the ex- pression of C9ORF72-derived poly(GR) protein. A Drosophila genetic screen identified key RQC fac- tors as potent modifiers of poly(GR)-induced neu- rodegeneration. ZNF598 overexpression in human neuroblastoma cells inhibited the nuclear accumu- lation of poly(GR) protein and decreased its cy- totoxicity, whereas ZNF598 deletion had opposing effects. Poly(GR)-encoding sequences in the re- porter RNAs caused translational stalling and gen- erated ribosome-associated translation products, sharing molecular signatures with canonical RQC substrates. Furthermore, ZNF598 and listerin 1, the RQC E3 ubiquitin-protein ligase, promoted poly(GR) degradation via the ubiquitin-proteasome pathway. An ALS-relevant ZNF598R69C mutant displayed loss- of-function effects on poly(GR) expression, as well as on general RQC. Moreover, RQC function was im- paired in C9-ALS patient-derived neurons, whereas lentiviral overexpression of ZNF598 lowered their poly(GR) expression and suppressed proapoptotic caspase-3 activation. Taken together, we propose that an adaptive nature of the RQC-relevant ZNF598 activity allows the co-translational surveillance to cope with the atypical expression of pathogenic poly(GR) protein, thereby acquiring a neuroprotec- tive function in C9-ALS/FTD.