ER proteostasis disturbances in Parkinson's disease: novel insights

Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta (SNpc). Proteostasis impairment at the level of the endoplasmic reticulum (ER) is emerging as a driving factor of dopaminergic neuron loss in PD. ER stress engages the activation of an adaptive reaction known as the unfolded protein response (UPR) to recover proteostasis or trigger apoptosis of damaged cells. The therapeutic potential of the UPR as a target has been recently validated using pharmacological and gene therapy approaches. A complex view is emerging where ER stress may have a dual role in PD, both in maintaining cell survival during initial stages of the diseases and trigger neuronal degeneration when the stress levels are sustained. Here we overview recent advances in determining the impact of ER stress to PD. PD is a progressive neurodegenerative disease that affects movement control, characterized by the loss of dopaminergic neurons in the SNpc. In most PD cases the presence of intracellular inclusions, termed Lewy bodies (LBs) is observed, where fibrillar aggregates of αSynuclein constitute a major component. Many cellular processes are altered in PD, including redox control, mitochondrial function, autophagy/lysosomal function, protein quality control mechanisms, and vesicle trafficking, among other processes. Accumulating evidence supports disruption in the secretory pathway as a triggering factor of proteostasis dysfunction in PD, mediating in part the selective degeneration of dopaminergic neurons (Chua and Tang, 2013; Mercado et al., 2013). Importantly, in addition to PD, ER stress is emerging as a relevant driver of most common neurodegenerative diseases (Hetz and Mollereau, 2014). ER stress activates the UPR, a complex signaling transduction pathway that mediates cellular adaptation to restore ER function (reviewed in Ron and Walter, 2007; Hetz, 2012). In this article we discuss recent insights on the significance of ER stress as a driver of dopaminergic neuron loss in PD and the potential of targeting UPR components to augment the homeostatic capacity of the ER and reduce pro-apoptotic signals.