Post-mortem analyses of human brain tissue samples from patients suffering from neurodegenerative disorders have demonstrated dysfunction of the endoplasmic reticulum (ER). A common characteristic of the aforementioned disorders is the intracellular accumulation and aggregation of proteins due to genetic mutations or exogenous factors, leading to the activation of a stress mechanism known as the unfolded protein response (UPR). This mechanism aims to restore cellular homeostasis, however, if prolonged, can trigger pro-apoptotic signals, which are thought to contribute to neuronal cell death. The authors present evidence to support the role of ER stress-induced apoptosis in Alzheimer's, Parkinson's and Huntington's diseases, and further examine the interplay between ER dyshomeostasis and mitochondrial dysfunction, and the function of reactive oxygen species (ROS) and calcium ions (Ca(2+)) in the intricate relationship between the two organelles. Possible treatments for neurodegenerative diseases that are based on combating ER stress are finally presented.
"The major symptoms involve motor dysfunction (reviewed in ). One of the mechanisms that affect the survival of dopaminergic neurons in Parkinson's disease is associated with dysregulation of Ca 2+ levels, especially in the ER and mitochondria . One of the consequences of perturbing Ca 2+ homeostasis is the accumulation of unfolded/misfolded proteins in the ER lumen. "
[Show abstract][Hide abstract] ABSTRACT: In this review we describe the present knowledge about store operated Ca2 + entry (SOCE) in neurons and the proteins involved in this process: STIM, as well as Orai and TRP channels. We address the issue of whether SOCE is used only to refill Ca2 + in the ER or whether Ca2 + that enters the neuronal cell during SOCE also performs signaling functions. We collected the data indicating that SOCE and its components participate in the important processes in neurons. This has implications for identifying new drug targets for the treatment of brain diseases. Evidence indicates that in neurodegenerative diseases Ca2 + homeostasis and SOCE components become dysregulated. Thus, different targets and strategies might be identified for the potential treatment of these diseases. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 01/2015; 740(9). DOI:10.1016/j.bbamcr.2015.01.019 · 5.02 Impact Factor
"In this regard, a wide range of inflammatory markers, either absent or minimally expressed in the healthly population, have been found present in AD, MS, PD, HD, ALS and MSA –. Additionally, oxidative stress, marked by lipid peroxidation, nitration, reactive carbonyls, and nucleic acid oxidation, is perhaps the earliest feature of neurodegeneration ,  and occurs in vulnerable neurons preceding any defining classical pathology. "
[Show abstract][Hide abstract] ABSTRACT: Neurodegenerative diseases comprise both hereditary and sporadic conditions characterized by an identifying progressive nervous system dysfunction and distinctive neuopathophysiology. The majority are of non-familial etiology and hence environmental factors and lifestyle play key roles in their pathogenesis. The extensive use of and ever increasing worldwide demand for electricity has stimulated societal and scientific interest on the environmental exposure to low frequency electromagnetic fields (EMFs) on human health. Epidemiological studies suggest a positive association between 50/60-Hz power transmission fields and leukemia or lymphoma development. Consequent to the association between EMFs and induction of oxidative stress, concerns relating to development of neurodegenerative diseases, such as Alzheimer disease (AD), have been voiced as the brain consumes the greatest fraction of oxygen and is particularly vulnerable to oxidative stress. Exposure to extremely low frequency (ELF)-EMFs are reported to alter animal behavior and modulate biological variables, including gene expression, regulation of cell survival, promotion of cellular differentiation, and changes in cerebral blood flow in aged AD transgenic mice. Alterations in inflammatory responses have also been reported, but how these actions impact human health remains unknown. We hence evaluated the effects of an electromagnetic wave (magnetic field intensity 1mT; frequency, 50-Hz) on a well-characterized immortalized neuronal cell model, human SH-SY5Y cells. ELF-EMF exposure elevated the expession of NOS and O2-, which were countered by compensatory changes in antioxidant catylase (CAT) activity and enzymatic kinetic parameters related to CYP-450 and CAT activity. Actions of ELF-EMFs on cytokine gene expression were additionally evaluated and found rapidly modified. Confronted with co-exposure to H2O2-induced oxidative stress, ELF-EMF proved not as well counteracted and resulted in a decline in CAT activity and a rise in O2- levels. Together these studies support the further evaluation of ELF-EMF exposure in cellular and in vivo preclinical models to define mechanisms potentially impacted in humans.
PLoS ONE 08/2014; 9(8):e104973. DOI:10.1371/journal.pone.0104973 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ER stress is activated in a number of important diseases such as diabetes, cancer, and neurodegeneration, but the molecular interactions governing the response are still being elucidated. In the absence of stress, protein complexes exist between the ER-resident chaperone BiP and three transmembrane signalling molecules which are responsible for signal transmission. Previous results suggested that cofactors might participate in these interactions, but the molecular details are not well understood. We coexpressed BiP and the lumenal domains of each of the three ER stress transducers and copurified the complexes in the presence of ATP and ADP in order to better understand how the complex is formed. ATP, but not ADP, was required to isolate the BiP-IRE1 and the BiP-PERK complexes, but the BiP-ATF6 complex was purified in all conditions tested. Based on the results, we hypothesize that in contrast to its mode of binding ATF6 and unfolded proteins, BiP binds to IRE1 and PERK in a different manner.
Biochemical and Biophysical Research Communications 03/2012; 420(2):473-8. DOI:10.1016/j.bbrc.2012.03.030 · 2.30 Impact Factor
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