Endoplasmic reticulum stress response and neurodegeneration
Introduction
Acute pathological states of the brain including ischemia and brain trauma have been identified as risk factors for the development of degenerative diseases, implying that common underlying mechanisms bring about cell injury in both cases [1], [2]. Protein aggregates that are hallmarks of degenerative disorders of the brain have also been found after transient cerebral ischemia, suggesting that the reactions of protein folding and processing are disturbed in such diseases [3], [4]. A major site for folding and processing of newly synthesized proteins is the endoplasmic reticulum (ER). The ER has been known for decades to be a sub-cellular compartment playing a central role in cellular calcium storage and signaling [5], [6]. The high calcium activity found in the ER lumen compared to that of the cytoplasm [7] is important not only for calcium signaling but also for the folding and processing of newly synthesized proteins, since these are strictly calcium-dependent reactions requiring high calcium activity for correct functioning [8], [9]. When protein folding and processing reactions are impaired, unfolded proteins accumulate in the ER. This is the warning signal that activates the unfolded protein response (UPR [10]). Activation of UPR is therefore taken as an indicator that ER function is disturbed in the pathological process under investigation. Activation of UPR has been found in various pathological states of the brain including ischemia and degenerative diseases, as discussed below. This review summarizes new observations implying that impairment of ER functioning is a common denominator of neuronal cell injury in various pathological states of the brain.
Section snippets
ER stress and ER stress response
Besides calcium storage and signaling, a central function of the ER is the folding and processing of newly synthesized membrane and secretory proteins. These are strictly calcium-dependent processes that require high calcium activity for correct functioning [8], [9]. When these functions are impaired (a pathological state termed ER stress), unfolded proteins accumulate in the ER lumen. Accumulation of unfolded proteins in the ER is a severe form of stress that will induce apoptosis if ER
Cerebral ischemia
The observation that the response of neuronal cells to an isolated impairment of ER functioning is in many respects identical to the response of the brain to transient ischemia led to the hypothesis that ischemia causes ER dysfunction [19], [20], [21]. This view is corroborated by the observations that transient cerebral ischemia triggers phosphorylation of PERK [22], [23], induces splicing of xbp1 mRNA indicative of IRE1 phosphorylation [24], activates caspase-12 [17], and induces expression
Conclusion
Evidence has been presented in various experimental studies that impairment of ER functioning may be involved in the pathological process culminating in neuronal cell death in a number of acute disorders and degenerative diseases of the brain. Preventing ER dysfunction or restoring ER functioning might block the pathological process at an early stage. Various avenues can be envisaged for therapeutic interventions, including strategies to render cells more resistant to conditions associated with
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2022, Smart Materials in MedicineCitation Excerpt :Novel therapeutic strategies, aiming at slowing down the neuronal cell loss in the progression of the neurodegenerative diseases, consider the involved subcellular and molecular-level mechanisms of these disorders [18,19]. Endoplasmic reticulum (ER) stress is an impairment of the ER membrane functioning that is associated with the pathogenic mechanisms of a number of diseases including the neurodegenerative Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis (ALS), brain ischemia, and various peripheral neuropathies [20–27]. The endoplasmic reticulum organelle comprises a three-dimensional (3D) membrane structure, which plays a key role in protein maturation, the intracellular trafficking of secreted and membrane-associated proteins, as well as in protein modification [28–30].
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