Abstract
Under physiological conditions, the endoplasmic reticulum (ER) is a central subcellular compartment for protein quality control in the secretory pathway that prevents protein misfolding and aggregation. Instrumental in protein quality control in the ER is the unfolded protein response (UPR), which is activated upon ER stress to reestablish homeostasis through a sophisticated transcriptionally and translationally regulated signaling network. However, this response can lead to apoptosis if the stress cannot be alleviated. The presence of abnormal protein aggregates containing specific misfolded proteins is recognized as the basis of numerous human conformational disorders, including neurodegenerative diseases. Here, I will highlight the overwhelming evidence that the presence of specific aberrant proteins in Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), prion diseases, and Amyotrophic Lateral Sclerosis (ALS) is intimately associated with perturbations in the ER protein quality control machinery that become incompetent to restore protein homeostasis and shift adaptive programs toward the induction of apoptotic signaling to eliminate irreversibly damaged neurons. Increasing our understanding about the deadly crosstalk between ER dysfunction and protein misfolding in these neurodegenerative diseases may stimulate the development of novel therapeutic strategies able to support neuronal survival and ameliorate disease progression.
Highlights
ISRN Cell Biology protein is a member of the bZIP family of transcription factors that activates the expression of several unfolded protein response (UPR) target genes involved in antioxidant responses, such as the transcription factor Nrf2, apoptosis, and autophagy [11, 12]
In endoplasmic reticulum (ER) stressed cells, activating transcription factor 6 (ATF6) is cleaved at the Golgi apparatus, and the released cytosolic domain translocates to the nucleus where it increases the expression of ER chaperones, ERAD-related genes, and proteins involved in organelle biogenesis [13]
This study showed that toxic turn Aβ and glucose-regulated protein 78 (GRP78) were detected in the neurons of young 3xTg-Alzheimer’s disease (AD) mice that were cognitively unimpaired while high-molecular weight Aβ oligomers were detected in the neurons of older mice with apparent memory dysfunction
Summary
The ER is the main intracellular Ca2+ reservoir in mammalian cells due to the concerted action of Ca2+ pumps that allow active Ca2+ uptake, Ca2+-binding proteins that allow the storage of significant amounts of Ca2+ in ER lumen, and Ca2+ channels that allow a controlled release of Ca2+ into the cytosol in response to well-known stimuli [18, 19]. An increase in the distance between the two compartments inhibits Ca2+ flux to the mitochondrial matrix, compromising Ca2+-dependent regulation of mitochondrial metabolism and ATP production, leading to cell death, and, on the other hand, decreasing the space between both organelles promotes mitochondrial Ca2+ overload that can lead to changes in the permeability of the outer mitochondrial membrane, release of proapoptotic factors like cytochrome c, leading to apoptosome formation, caspase activation, and apoptosis induction [39]. During the adaptive phase of ER stress, an early increase in cellular bioenergetics and mitochondrial metabolism was shown to occur, but during the cell death response, ER stress was found to exert profound deleterious effects on mitochondrial function and to activate an apoptotic pathway, which depends upon Ca2+ transfer from the ER to the mitochondria [40, 41]. Apoptosis associated with chronic ER stress may contribute to pathophysiological processes involved in a number of prevalent diseases, including neurodegenerative diseases [49, 63]
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