URG7-Driven Homeostatic Adaptation Protects SH-SY5Y Cells from 6-OHDA Neurotoxicity

Parkinson's disease (PD) is characterized by progressive dopaminergic neurodegeneration associated with oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and impaired proteostasis. In this study, we investigated the role of Up-Regulated Gene 7 (URG7), an ER-resident protein, in regulating cellular stress responses in SH-SY5Y neuroblastoma cells exposed to 6-hydroxydopamine (6-OHDA), a widely used in vitro model of PD. URG7 overexpression significantly enhanced activation of the adaptive unfolded protein response (UPR), particularly the PERK/eIF2α/ATF4 pathway, while limiting ER stress-induced damage. Moreover, URG7 promoted protein quality control mechanisms by stimulating both the ubiquitin-proteasome system and autophagy, as demonstrated by increased ubiquitination, proteasome activity, and upregulation of Beclin-1 and LC3-II. URG7 also prevented intracellular calcium overload and reduced the expression of proteins involved in the SOCE pathway, thereby preserving calcium homeostasis under oxidative stress conditions. In addition, URG7 attenuated G1 cell cycle arrest and reduced the expression of pro-apoptotic markers, including p53, p21, Bax, and cleaved PARP, while promoting pro-survival signaling pathways such as AKT and ERK1/2. Collectively, these findings identify URG7 as an important regulator of adaptive stress responses and suggest its possible involvement in neuroprotective mechanisms associated with neurodegenerative disorders characterized by oxidative stress.