Abstract
OPINION article Front. Aging Neurosci., 27 March 2015Sec. Parkinson’s Disease and Aging-related Movement Disorders https://doi.org/10.3389/fnagi.2015.00039
Highlights
Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta (SNpc)
The unfolded protein response (UPR) is a signaling network mediated by the activation of three stress sensors located at the endoplasmic reticulum (ER) membrane, including inositol requiring kinase 1α (IRE1α), activating transcription factor 6 (ATF6), and protein kinase RNA-like ER kinase (PERK) (Figure 1A)
There are many other studies linking other PD genes with alteration of the secretory pathway, including LRRK2, Parkin, Pael-R, DJ-1, ATP13A2, and VPS35 (Zimprich et al, 2011). These reports suggest that secretory pathway dysfunction is a common hallmark of PD, which may result in pathological levels of ER stress contributing to the etiology of the disease
Summary
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. 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.
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