Abstract
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, and it is characterized by the selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), as well as the presence of intracellular inclusions with α-synuclein as the main component in surviving DA neurons. Emerging evidence suggests that the imbalance of proteostasis is a key pathogenic factor for PD. Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and autophagy, two major pathways for maintaining proteostasis, play important roles in PD pathology and are considered as attractive therapeutic targets for PD treatment. However, although ER stress/UPR and autophagy appear to be independent cellular processes, they are closely related to each other. In this review, we focused on the roles and molecular cross-links between ER stress/UPR and autophagy in PD pathology. We systematically reviewed and summarized the most recent advances in regulation of ER stress/UPR and autophagy, and their cross-linking mechanisms. We also reviewed and discussed the mechanisms of the coexisting ER stress/UPR activation and dysregulated autophagy in the lesion regions of PD patients, and the underlying roles and molecular crosslinks between ER stress/UPR activation and the dysregulated autophagy in DA neurodegeneration induced by PD-associated genetic factors and PD-related neurotoxins. Finally, we indicate that the combined regulation of ER stress/UPR and autophagy would be a more effective treatment for PD rather than regulating one of these conditions alone.
Highlights
Parkinson’s disease (PD), the most common neurodegenerative movement disorder, affects approximately 1% of the population over 60 years old, and its incidence dramatically increases to approximately 5% in the population greater than 85 years of age (Li and Le, 2020; Wang et al, 2020b)
Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and autophagy, two major pathways that respond to an imbalance in cellular homeostasis, play important roles in the pathology of neurodegenerative diseases including PD (Karabiyik et al, 2017; Costa et al, 2020)
The UPR is controlled by three ER-resident sensors: inositolrequiring kinase 1α (IRE1α), protein kinase RNA-activated (PKR)-like ER kinase (PERK), and activating transcription factor 6 (ATF6) (Manie et al, 2014)
Summary
Parkinson’s disease (PD), the most common neurodegenerative movement disorder, affects approximately 1% of the population over 60 years old, and its incidence dramatically increases to approximately 5% in the population greater than 85 years of age (Li and Le, 2020; Wang et al, 2020b). Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and autophagy, two major pathways that respond to an imbalance in cellular homeostasis, play important roles in the pathology of neurodegenerative diseases including PD (Karabiyik et al, 2017; Costa et al, 2020). Dysfunctions, the cells sense the ER stress and subsequently initiate an adaptive response referred to as UPR This in turn attempts to alleviate ER stress by enhancing the protein-folding capacity and reducing the general synthetic load to restore ER homeostasis and maintain cell survival (Xu et al, 2012; Rashid et al, 2015). The UPR is controlled by three ER-resident sensors: inositolrequiring kinase 1α (IRE1α), protein kinase RNA-activated (PKR)-like ER kinase (PERK), and activating transcription factor 6 (ATF6) (Manie et al, 2014). If the adaptive UPR fails to restore ER homeostasis, UPR signaling undergoes continuous activation to initiate prodeath signals through multiple pathways that eventually trigger intrinsic apoptosis (Hetz and Papa, 2018)
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