Research Article: GRP78/BIP/HSPA5 as a Therapeutic Target in Models of Parkinson’s Disease: A Mini Review

Date Published: March 5, 2019

Publisher: Hindawi

Author(s): Adaze Bijou Enogieru, Sylvester Ifeanyi Omoruyi, Donavon Charles Hiss, Okobi Eko Ekpo.


Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by selective loss of dopamine neurons in the substantia nigra pars compacta of the midbrain. Reports from postmortem studies in the human PD brain, and experimental PD models reveal that endoplasmic reticulum (ER) stress is implicated in the pathogenesis of PD. In times of stress, the unfolded or misfolded proteins overload the folding capacity of the ER to induce a condition generally known as ER stress. During ER stress, cells activate the unfolded protein response (UPR) to handle increasing amounts of abnormal proteins, and recent evidence has demonstrated the activation of the ER chaperone GRP78/BiP (78 kDa glucose-regulated protein/binding immunoglobulin protein), which is important for proper folding of newly synthesized and partly folded proteins to maintain protein homeostasis. Although the activation of this protein is essential for the initiation of the UPR in PD, there are inconsistent reports on its expression in various PD models. Consequently, this review article aims to summarize current knowledge on neuroprotective agents targeting the expression of GRP78/BiP in the regulation of ER stress in experimental PD models.

Partial Text

Parkinson’s disease (PD) is a neurological disorder characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain, resulting in loss of dopamine in the striatum. In patients with PD, there are four primary motor symptoms which include tremor at rest, postural instability, rigidity, and bradykinesia [1]. PD was previously considered to be a condition that affects only the motor system, but with more research, it is now known to be a multifaceted disorder with diverse clinical features that include sleep, cognitive, and neuropsychiatric disorders [2, 3].

The ER stress pathway or unfolded protein response (UPR) is known to handle growing quantities of aberrant proteins in the ER [25]. This response program is tasked with the reduction of misfolded/abnormal proteins through various mechanisms (Figure 1). Firstly, GRP78/BiP disassociates from the ER stress sensors, namely, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1) to initiate the ER stress response. Following dissociation of GRP78/BiP, autophosphorylation and activation of PERK facilitate the phosphorylation of eukaryotic translation initiation factor 2a (eIF2a) to inhibit further protein synthesis and translation [26–28]. ATF6 is cleaved in the Golgi after translocation from the ER and then migrates into the nucleus to upregulate ER chaperones such as GRP78/BiP and 94 kDa glucose-regulated protein (GRP94) which enhances the folding capacity of the ER [29]. Also, IRE1 is involved in endoribonuclease activity and activates X-box binding protein 1 (XBP-1) to promote ER-associated degradation [30–32].

GRP78/BiP is a key chaperone essential for proper functioning of the ER and in various cellular processes [36–38]. Most notable is its dual role of regulating protein folding and the initiation of UPR signaling in the ER [39]. In PD, there are inconsistent reports on the expression of GRP78/BiP in various experimental models. For instance, treatment of MN9D cells with a neurotoxin 1-methyl-4-phenylpyridinium (MPP+; Figure 3) resulted in a reduction of GRP78/BiP expression, while treatment of SH-SY5Y cells with a different neurotoxin 6-hydroxydopamine (6-OHDA; Figure 3) increased its expression [40, 41]. In a PD model using MPP+-treated rabbits, Ghribi and colleagues revealed the translocation of GRP78/BiP to the nucleus and cytosol from the ER as well as a significant decrease in TH-positive cells in the SNpc [42]. In a different study, Shimoke and coworkers demonstrated an increase in the expression of GRP78/BiP after exposure to tunicamycin; however, they observed no increase in the expression of GRP78/BiP in PC12 cells after treatment with a neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; Figure 3), for 24 hours [43]. Duan and Mattson utilized the MPTP-treated mouse model of PD to demonstrate that the upregulation of GRP78/BiP by 2-deoxy-d-glucose significantly prevented loss of dopamine neurons [44].

Over the years, the use of neurotoxin-based experimental models of PD has contributed extensively to the understanding of PD and human health. For instance, such neurotoxins as MPTP, MPP+, 6-OHDA, paraquat, and rotenone have been utilized in the search, identification, and development of novel therapeutic agents in PD [60]. Also, the MPTP mouse and 6-OHDA rat models of PD have contributed immensely to the translation of animal experimentation into clinical practice and are still very much important for investigating different mechanisms of neuronal degeneration in PD. Considerable evidence shows that some experimental therapeutic agents have substantial antioxidant and anti-inflammatory activities, thus demonstrating an inhibitory effect in the oxidative and inflammatory mechanisms linked to neuronal loss in PD [61, 62].

Protein misfolding and aggregation is implicated in the pathogenesis of PD, and the regulation of GRP78/BiP is critical for proper functioning of the UPR. As highlighted in this review, several studies have attempted to unravel the mechanism behind ER stress by targeting GRP78/BiP and the UPR as a way of halting dopaminergic neuronal loss in PD. Although it is established that GRP78/BiP is an essential chaperone in the UPR, studies discussed in this review indicate that the expression of GRP78/BiP is altered in various models of PD depending on the cell type and toxin used in inducing neuronal damage. Consequently, various neuroprotective agents induce the upregulation or downregulation of GRP78/BiP in response to the ER stress-inducing agent in these PD models to promote the survival of dopaminergic neurons. Also, evidence from this review indicate that a translational potential exists for the regulation of GRP78/BiP activity; however, further investigations are needed to properly understand the involvement of GRP78/BiP in the protection of neurons against degeneration in PD. This knowledge would be valuable in designing novel remedies targeted at combating PD and other neurodegenerative disorders linked to the aggregation of misfolded proteins.




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