Chaperone-Dependent Mechanisms as a Pharmacological Target for Neuroprotection

Abstract

Modern pharmacotherapy of neurodegenerative diseases is predominantly symptomatic and does not allow vicious circles causing disease development to break. Protein misfolding is considered the most important pathogenetic factor of neurodegenerative diseases. Physiological mechanisms related to the function of chaperones, which contribute to the restoration of native conformation of functionally important proteins, evolved evolutionarily. These mechanisms can be considered promising for pharmacological regulation. Therefore, the aim of this review was to analyze the mechanisms of endoplasmic reticulum stress (ER stress) and unfolded protein response (UPR) in the pathogenesis of neurodegenerative diseases. Data on BiP and Sigma1R chaperones in clinical and experimental studies of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease are presented. The possibility of neuroprotective effect dependent on Sigma1R ligand activation in these diseases is also demonstrated. The interaction between Sigma1R and BiP-associated signaling in the neuroprotection is discussed. The performed analysis suggests the feasibility of pharmacological regulation of chaperone function, possibility of ligand activation of Sigma1R in order to achieve a neuroprotective effect, and the need for further studies of the conjugation of cellular mechanisms controlled by Sigma1R and BiP chaperones.

Neuroprotective Effect of Antiapoptotic URG7 Protein on Human Neuroblastoma Cell Line SH-SY5Y

“…This chaperonin serves several functions associated with cell survival, and in particular, it controls the folding and assembly of proteins within the ER and prevents the transport of incorrectly folded proteins/protein subunits [ 22 , 23 ]. Interestingly, among the etiopathogenetic factors of neurodegenerative diseases, the lack of maintenance of protein folding plays a crucial role, therefore suggesting the pharmacological regulation of the chaperones’ function as a therapeutic strategy [ 24 ]. We also demonstrated that all three arms of the UPR are activated by URG7.…”

Hybrid neural network approaches to predict drug–target binding affinity for drug repurposing: screening for potential leads for Alzheimer’s disease

“…A substantial body of evidence suggests that S1R, in combination with BIP, a regulator of endoplasmic reticulum stress (ERS), plays a pivotal role in the ERS pathway, which is a component of cellular stress and a core mechanism underlying synaptic loss and neurodegeneration in AD pathology ( Ortega-Roldan et al, 2013 ; Venkataraman et al, 2022) . S1R-dependent neuroprotection is likely to be mediated by the regulation of the unfolded protein response (UPR) in ERS ( Voronin et al, 2023) . Under ERS conditions, S1R agonists promote the dissociation of S1R-BIP calcium ion-sensitive chaperone complexes, resulting in enhanced chaperone activity of BIP toward misfolded proteins and S1R binding to client protein IRE1 α .…”

“…The regulatory effect of S1R agonists can increase the expression of BIP and brain-derived neurotrophic factor (BDNF) and decrease the expression of pro-inflammatory interleukin-6 (IL-6) ( Hayashi and Su, 2007 ; Rosen et al, 2019 ; Zhemkov et al, 2021) . Thus, S1R agonist regulation presents a viable strategy for the neuroprotective treatment of AD, aimed at reducing ERS and neuroinflammation while enhancing neural plasticity ( Voronin et al, 2023) .…”

“…Previous studies have suggested that sigma-1 receptor (S1R) has neuroprotective effects and that its physiological function has a direct impact on endogenous neuroprotective mechanisms ( Voronin et al, 2023) . As a protein chaperone, S1R locates on specialized lipid rafts of mitochondria-associated endoplasmic reticulum membranes (MAMs), which are known to form mitochondrial endoplasmic reticulum contacts (MERCs) with the outer mitochondrial membrane and play a role in various biochemical processes, such as autophagosome formation, cellular energy production, and maintenance of IR 3 R 3-dependent calcium homeostasis.…”

Strategies targeting endoplasmic reticulum stress to improve Parkinson’s disease

“…MPP + has been shown to reduce the expression of BIP in SH-SY5Y cells (Ai et al, 2023), while 6-OHDA has been shown to increase the expression of BIP in neurons (Holtz and O'Malley, 2003). Therefore, more chaperones should be included in studies to discover more effective compounds, such as chaperone PDI and Sigma1R (Perri et al, 2015;Voronin et al, 2023). In addition, the improvement of protein folding by adding chaperones should be verified through more aspects such as electron microscopy observation or structural analysis after protein purification, to increase the convincingness.…”