The ER stress response is triggered by insults underlying also various neurodegenerative disorders. Schematic view of changes and interactions during ER stress and the link to the ubiquitin proteasome system (UPS). 11 In the following, we will review studies on ER stress and its function in different neurodegenerative diseases by analyzing data gathered about molecular mechanisms and cellular pathways involving the ER and discuss how these cellular events may contribute to the disease process in human neurological disorders.ĮR stress and neurodegenerative disease. 2, 3, 10 Level of intracellular calcium and calcium release from the ER are important in ER–mitochondrial interactions and in the control of cell death ( Figure 1). 4, 5, 9 To this come effects of environmental toxins, reactive oxygen species (ROS) and other signals that influence mitochondria and lead to activation of the caspase family of cysteine proteases causing cell death. 7, 8 Dysfunctional UPS in turn cause more accumulation of proteins in the cell leading also to ER stress and aggravation of the disease. 7, 8 It is generally thought that the activity of UPS is mitigated in these diseases either by the protein aggregates or by enhanced oxidative stress and other toxic products. 4, 5, 6Ī common sign of many neurodegenerative diseases is the accumulation and deposits of misfolded proteins that affects various cell signaling systems, as well as neuronal connectivity and cell death. 2, 3 It is known that disturbed functions of the ubiquitin proteasome system (UPS), responsible for the degradation of cytosolic, ER and synaptic proteins, can contribute to ER stress. 1, 2, 3 The cellular signals involved in ER stress-mediated cell death and apoptosis are complex and yet not fully understood. 1, 2, 3 However, if the function of the ER is severely impaired, genes and pathway leading to cell death and/or inhibition of survival are also activated. In general, the UPR changes the expressions of specific proteins, such as those for the ER chaperones, enhances degradation of misfolded (mutant or unfolded) protein, and inhibits protein synthesis to decrease the load within the ER. 1, 2, 3 The UPR and its signaling components are described in great detail in recent reviews. ER stress activates signaling pathways including the unfolded protein response (UPR) that counteracts the effects of the original stress having either an environmental or genetic cause. 1, 2, 3 Disturbance in the function or loss of integrity of the ER leads to ER stress that can be caused, for example, by accumulation of unfolded proteins and by changes in calcium homeostasis within the ER.
1, 2, 3 The ER exerts a quality control of proteins ensuring correct handling of the final product that is crucial for normal cell function. Endoplasmic reticulum (ER) is an important organelle for the synthesis, correct folding, post-translation modification and transport of nascent proteins to different destinies.
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