The UPRERgoverns the cell-specific response of human dopaminergic neurons to mitochondrial stress

Abstract Mitochondrial dysfunction is thought to be central to the pathophysiology of Parkinson’s disease. The preferential vulnerability of dopaminergic (DA) neurons of the substantia nigra pars compacta to mitochondrial stress may underlie their massive degeneration and the occurrence of motor symptoms. Using LUHMES-derived DA neurons, we demonstrated that inhibition of the mitochondrial electron transport chain resulted in a severe alteration of mitochondrial turnover, pushing the balance towards mitochondrial loss, a reduction of the maturation status of the DA population and an increased proportion of apoptotic cells. PERK-mediated Unfolded Protein Response of the Endoplasmic Reticulum (UPR ER ) emerged as the key coordinator of the stress response, governing the inactivation of the mitochondrial UPR (UPR mt ), the initiation of mitophagy and the cell-specific expression of long non-coding RNAs (lncRNAs). Importantly, we discovered novel lncRNAs specifically expressed in human DA neurons upon stress. Among them, we showed that lnc-SLC6A15-5 contributes to the resumption of translation after mitochondrial stress. Summary The Unfolded Protein Response of the Endoplasmic Reticulum is induced upon stress in human dopaminergic neurons and modulates mitochondrial homeostasis and transcriptional programs including expression of long non-coding RNAs (lncRNAs). We discovered a lncRNA involved in translation resumption after stress.