Radiation myelitis is the most serious complication in clinical radiotherapy for spinal metastases. We previously showed that I-125 brachytherapy induced apoptosis of spinal cord neurons accompanied by autophagy. In this study, we further investigated the mechanism by which I-125 radiation triggered autophagy in neural cells. We found that autophagy induced by I-125 radiation was involved in endoplasmic reticulum (ER) stress and mainly dependent on PERK-eIF2 alpha pathway. The expressions of LC3II, ATG12 and PI3K were significantly suppressed in PERK knockout neural cells. Meanwhile, the expressions of phosphorylated-Akt s473 and caspase 3/8 all significantly increased in neural cells transfected with a PERK siRNA and which enhanced apoptosis of neurons after I-125 radiation. The results were consistent with that by MTT and Annexin-FITC/PT staining. In annimal model of banna pigs with radiation myelitis caused by I-125 brachytherapy, we have successfully decreased PERK expression by intrathecal administration of the lentivirus vector. The apoptosis rate was significantly higher than that in control group and which deteriorated radiation myelitis of banna pigs. Thus, autophagy caused by I-125 radiation was mainly as an attempt of cell survival at an early stage, but it would be a self-destructive process and promoted the process of apoptosis and necrosis radiated by I-125 for more than 72 hours. The study would be useful and helpful to maximize efficiency of radiation therapy in clinical therapy.