Autophagy and Cell Death in Alzheimer’s, Parkinson’s and Prion Diseases

Neurodegenerative brain disorders (NBD) impair brain cells’ proteostasis with the accumulation of normal, mutant, misfolded or unfolded proteins in the endoplasmic reticulum (ER). The increased ER burden of these proteins elicits the unfolded protein response (UPR) and stimulates autophagy (AUT). In the short term, UPR and AUT attenuate ER’s burden. With prolonged ER stress, the UPR changes from supporting cell survival to promoting apoptosis. The failure of the UPR, to meet the increased protein burden, leads to an increase in cytosolic protein accumulation that initially further stimulates AUT. Over time, the accumulated proteins in the cytosol undergo post-translational changes into toxic monomers and oligomers that repress AUT at multiple levels and promote cell death. This review describes the interlinked signalling pathways of AUT, apoptosis and necroptosis and their modulation by Alzheimer’s, Parkinson’s and prion diseases and outlines the pharmacological strategies for targeting AUT, apoptosis and necroptosis signalling pathways

Beneficial Role of ROS in Cell Survival: Moderate Increases in H2O2 Production Induced by Hepatocyte Isolation Mediate Stress Adaptation and Enhanced Survival

High levels of reactive oxygen species (ROS) can lead to impairment of cell structure, biomolecules’ loss of function and cell death and are associated with liver diseases. Cells that survive increased ROS often undergo malignant transformation. Many cancer cells tolerate high levels of ROS. Here we report a transiently increased production of H2O2 and concomitant upregulation of antioxidative enzymes triggered by hepatocyte isolation; the H2O2 levels revert in about two days in culture. Three-day survival rate of the isolated cells in the presence of 2.5-fold increase of H2O2 is almost 80%. Apoptosis activation through the mitochondrial pathway is meanwhile reduced by inhibition of caspase-9 triggering. This reduction depends on the amount of H2O2 production, as decreased production of H2O2 in the presence of an antioxidant results in increased apoptosis triggering. These stress adaptations do not influence urea production, which is unchanged throughout the normal and stress adapted phases. We conclude that hepatocytes’ stress adaptation is mediated by increased ROS production. In this case, high ROS improve cell survival

European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS).

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.The EU-ROS consortium (COST Action BM1203) was supported by the European Cooperation in Science and Technology (COST). The present overview represents the final Action dissemination summarizing the major achievements of COST Action BM1203 (EU-ROS) as well as research news and personal views of its members. Some authors were also supported by COST Actions BM1005 (ENOG) and BM1307 (PROTEOSTASIS), as well as funding from the European Commission FP7 and H2020 programmes, and several national funding agencies

Antioxidants, food processing and health

The loss and/or modification of natural antioxidants during various food processing techniques and storage methods, like heat/thermal, UV, pulsed electric field treatment, drying, blanching and irradiation is well described. Antioxidants in their reduced form are modified mainly by oxidation, and less by pyrolysis and hydrolysis. Thus, they are chemically converted from the reduced to an oxidized form. Here we describe the neglected role of the oxidized forms of antioxidants produced during food processing and their effect on health. While natural antioxidants in their reduced forms have many well studied health-promoting characteristics, much less is known about the effects of their oxidized forms and other metabolites, which may have some health benefits as well. The oxidized forms of natural antioxidants affect cell signaling, the regulation of transcription factor activities and other determinants of gene expression. Very low doses may trigger hormesis, resulting in specific health benefits by the activation of damage repair processes and antioxidative defense systems. Functional studies determining the antioxidants’ effects on the organisms are important, especially as reduced or oxidized antioxidants and their metabolites may have additional or synergistic effects

Healthy lifestyle recommendations

In this review, we describe the role of oxidized forms of nicotinamide adenine dinucleotide (NAD+ ) as a molecule central to health benefits as the result from observing selected healthy lifestyle recommendations. Namely, NAD+ level can be regulated by lifestyle and nutrition approaches such as fasting, caloric restriction, sports activity, low glucose availability, and heat shocks. NAD+ is reduced with age at a cellular, tissue, and organismal level due to inflammation, defect in NAMPT-mediated NAD+ biosynthesis, and the PARP-mediated NAD+ depletion. This leads to a decrease in cellular energy production and DNA repair and modifies genomic signalling leading to an increased incidence of chronic diseases and ageing. By implementing healthy lifestyle approaches, endogenous intracellular NAD+ levels can be increased, which explains the molecular mechanisms underlying health benefits at the organismal level. Namely, adherence to here presented healthy lifestyle approaches is correlated with an extended life expectancy free of major chronic diseases

Clinical implications of cellular stress responses

Cellular stress response is a reaction to changes or fluctuations of extracellular conditions that damage the structure and function of macromolecules. Different stressors trigger different cellular responses, namely induce cell repair mechanisms, induce cell responses that result in temporary adaptation to some stressors, induce autophagy or trigger cell death. Inability to repair the damage or exposure to prolonged stress may contribute to aging. Persistent cell stress often enhances susceptibility to cancer and aging associated diseases. Cells and tissues are increasingly being used for transplantations and other novel therapeutic methods in which the quality and well being of cells is of paramount importance for the treatment to succeed. Therefore, discovering the mechanisms of cellular stress responses and the ability to detect and ameliorate them is important in prevention of development of disorders developed by persistent stress and for the success of transplantation and other cell related methods of regenerative medicine

NAD+ as the link between oxidative stress, inflammation, caloric restriction, exercise, DNA repair, longevity, and health span

Oxidative stress and decreased DNA damage repair in vertebrates increase with age also due to lowered cellular NAD+. NAD+ depletion may play a major role in the aging process at the cellular level by limiting (1) energy production, (2) DNA repair, and (3) genomic signaling. In this study, we hypothesize that it is not NAD+ as a cofactor in redox reactions and coenzyme in metabolic processes that has the ultimate role in aging, but rather the role of NAD+ in cellular signaling when used as substrate for sirtuins (SIRT1-7 in mammals) and PARPs [Poly(ADP-ribose) polymerases]. Both sirtuins and PARPs influence many transcription factors and can affect gene expression. As a signaling molecule, NAD+ is consumed in the reaction donating ADP-ribose and releasing nicotinamide (NAM) as a by-product. It seems that aging at the cellular level is associated with a decline of NAD+ and that NAD+ restoration can reverse phenotypes of aging by inducing cellular repair and stress resistance. Adequate intracellular NAD+ concentrations may be an important longevity assurance factor, while lowered cellular NAD+ concentration may negatively influence the life span

Unfolded protein response and macroautophagy in Alzheimer\u27s, Parkinson\u27s and prion diseases

Proteostasis are integrated biological pathways within cells that control synthesis, folding, trafficking and degradation of proteins. The absence of cell division makes brain proteostasis susceptible to age-related changes and neurodegeneration. Two key processes involved in sustaining normal brain proteostasis are the unfolded protein response and autophagy. Alzheimer\u27s disease (AD), Parkinson\u27s disease (PD) and prion diseases (PrDs) have different clinical manifestations of neurodegeneration, however, all share an accumulation of misfolded pathological proteins associated with perturbations in unfolded protein response and macroautophagy. While both the unfolded protein response and macroautophagy play an important role in the prevention and attenuation of AD and PD progression, only macroautophagy seems to play an important role in the development of PrDs. Macroautophagy and unfolded protein response can be modulated by pharmacological interventions. However, further research is necessary to better understand the regulatory pathways of both processes in health and neurodegeneration to be able to develop new therapeutic interventions