Elsevier

Cell Calcium

Volume 38, Issues 3–4, September–October 2005, Pages 409-415
Cell Calcium

Endoplasmic reticulum stress response and neurodegeneration

https://doi.org/10.1016/j.ceca.2005.06.019Get rights and content

Abstract

The endoplasmic reticulum (ER) is a subcellular compartment playing a central role in calcium storage and signaling. Disturbances of ER calcium homeostasis constitute a severe form of stress interfering with central functions of this structure including the folding and processing of newly synthesized membrane and secretory proteins. Blocking the folding and processing reactions results in the accumulation of unfolded proteins forming potentially toxic aggregates. To restore ER functioning, specific stress responses are activated one of which is the unfolded protein response (UPR). UPR is characterized by a shutdown of global protein synthesis and activation of expression of genes coding for ER-resident proteins that are involved in the folding and processing reactions. ER calcium homeostasis is therefore inevitably associated with major cellular functions, including gene transcription and translation. ER calcium homeostasis und ER functions are believed to be impaired in various degenerative diseases of the brain including Alzheimer's, Parkinson's and Huntington's disease, and amyotrophic lateral sclerosis. ER functioning has also been shown to be disturbed in acute pathological states of the brain such as ischemia and trauma, which have been identified as risk factors for the development of degenerative diseases. This implies that there are common underlying pathomechanisms. This review will summarize new observations suggesting that impairment of ER functioning may be a common denominator of pathological processes resulting in neuronal cell injury in acute disorders and degenerative diseases of the brain.

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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      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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