α-Synuclein and neuronal cell death

Mutations in the DJ-1 gene have been linked to autosomal recessive familial Parkinson's disease. To understand the function of DJ-1, we determined the DJ-1 expression in both zebrafish and post mortem human brains. We found that DJ-1 was expressed early during zebrafish development and throughout adulthood. Knock down (KD) of DJ-1 by injection of morpholino did not cause dramatic morphologic alterations during development, and no loss of dopaminergic neurons was observed in embryos lacking DJ-1. However, DJ-1 KD embryos were more susceptible to programmed cell death. While a slight reduction in staining for islet-1 positive neurons was observed in both DJ-1 KD and H₂O₂ treated embryos, the number of apoptotic cells was significantly increased in both KD and H₂O₂ treated embryos. Interestingly, DJ-1 expression was increased in brains of zebrafish under conditions of oxidative stress, indicating that DJ-1 is a part of stress-responsive machinery. Since oxidative stress is one of the major contributors to the development of Alzheimer's disease (AD), we also examined DJ-1 expression in AD brains. Using DJ-1 specific antibodies, we failed to detect a robust staining of DJ-1 in brain tissues from control subjects. However, DJ-1 immunoreactivity was detected in hippocampal pyramidal neurons and astrocytes of AD brains. Therefore, our results strongly suggest that DJ-1 expression is not necessary during zebrafish development but can be induced in zebrafish exposed to oxidative stress and is present in human AD brains.     

Devil inside: does plant programmed cell death involve the endomembrane system?

Eukaryotic cells have to constantly cope with environmental cues and integrate developmental signals. Cell survival or death is the only possible outcome. In the field of animal biology, tremendous efforts have been put into the understanding of mechanisms underlying cell fate decision. Distinct organelles have been proven to sense a broad range of stimuli and, if necessary, engage cell death signalling pathway(s). Over the years, forward and reverse genetic screens have uncovered numerous regulators of programmed cell death (PCD) in plants. However, to date, molecular networks are far from being deciphered and, apart from the autophagic compartment, no organelles have been assigned a clear role in the regulation of cellular suicide. The endomembrane system (ES) seems, nevertheless, to harbour a significant number of cell death mediators. In this review, the involvement of this system in the control of plant PCD is discussed in‐depth, as well as compared and contrasted with what is known in animal and yeast systems.     

The end of autophagic cell death?

In the mammalian system, cell death is often preceded or accompanied by autophagic vacuolization, a finding that initially led to the widespread belief that so-called "autophagic cell death" would be mediated by autophagy. Thanks to the availability of genetic tools to disable the autophagic machinery, it has become clear over recent years that autophagy usually constitutes a futile attempt of dying cells to adapt to lethal stress rather than a mechanism to execute a cell death program. Recently, we systematically addressed the question as to whether established or prospective anticancer agents may induce "autophagic cell death". Although a considerable portion among the 1,400 compounds that we evaluated induced autophagic puncta and actually increased autophagic flux, not a single one turned out to kill tumor cells through the induction of autophagy. Thus, knockdown of essential autophagy genes (such as ATG5 and ATG7) failed to prevent and rather accelerated chemotherapy-induced cell death, in spite of the fact that this manipulation efficiently inhibits autophagosome formation. Herein, we review these finding and--polemically--raise doubts as to the very existence of "autophagic cell death".     

Astrocytes in Huntington's chorea: accomplice or guilty of the neuronal death?

Huntington's disease is an hereditary dominant neurodegenerative disorder clinically characterised by progressive motor deficits, personality changes, decreased mental capacity and death after about 15-20 years. Most studies are based on the research of intrinsic mechanisms that could be responsible for dysfunction and later degeneration of neuronal subsets. It is only in the last five years that more interest has been focused on another brain cell type : the astrocytes. This review presents evidence that astroglial function is also affected in Huntington's disease. Among the possible mechanisms, Huntington's disease mutation may alter the EGF receptor signaling pathway, that regulates the astrocytic response to neuronal injuries.     

DNA damage-induced cell death： lessons from the central nervous system

DNA damage can, but does not always, induce cell death. While several pathways linking DNA damage signals to mitochondria-dependent and -independent death machineries have been elucidated, the connectivity of these pathways is subject to regulation by multiple other factors that are not well understood. We have proposed two conceptual models to explain the delayed and variable cell death response to DNA damage： integrative surveillance versus autonomous pathways. In this review, we discuss how these two models may explain the in vivo regulation of cell death induced by ionizing radiation （IR） in the developing central nervous system, where the death response is regulated by radiation dose, cell cycle status and neuronal development.     

Giant cell formation: the way to cell death or cell survival?

The study of giant cells in populations of different tumor cells and evaluation of their role in cancer development is an expanding field. The formation of giant cells has been shown to be followed by mitotic catastrophe, apoptosis, necrosis, and other types of cell elimination. Reports also demonstrate that giant cells can escape cell death and give rise to new cancer cells. However, it is not known if the programmed cell death is involved in this type of cell cycle disorders. Here we describe principal events that are observed during giant cell formation. We also consider the role of giant cells in cancer development, taking into account both published work and our own recent data in this field.     

Does the position of the electron-donating nitrogen atom in the ring system influence the efficiency of a dye-sensitized solar cell? A computational study

Electronic structure of the XeOF₂ molecule and its two complexes with HX (X= F, Cl, Br, I) molecules have been studied in the gas phase using quantum chemical topology methods: topological analysis of electron localization function (ELF), electron density, ρ(r), reduced gradient of electron density |RDG(r)| in real space, and symmetry adapted perturbation theory (SAPT) in the Hilbert space. The wave function has been approximated by the MP2 and DFT methods, using APF-D, B3LYP, M062X, and B2PLYP functionals, with the dispersion correction as proposed by Grimme (GD3). For the Xe-F and Xe=O bonds in the isolated XeOF₂ molecule, the bonding ELF-localization basins have not been observed. According to the ELF results, these interactions are not of covalent nature with shared electron density. There are two stable F₂OXe^…HF complexes. The first one is stabilized by the F-H^…F and Xe^…F interactions (type I) and the second by the F-H^…O hydrogen bond (type II). The SAPT analysis confirms the electrostatic term, E_elst ⁽¹⁾ and the induction energy, E_ind ⁽²⁾ to be the major contributors to stabilizing both types of complexes.

     

The powerhouse takes control of the cell: Is the mitochondrial permeability transition a viable therapeutic target against neuronal dysfunction and death?

Stroke and neurodegenerative disease exert an increasing large toll on human health at the levels both of the individual and of society. As an example of each, in the United States, stroke is the major single cause of overall morbidity and mortality, and the financial costs of Alzheimer's disease alone dwarfs the entire federal medical research budget. It has been long recognized that mitochondrial energy production is essential for the second to second functions of the central nervous system (CNS), and that severe mitochondrial impairment is incompatible with normal cerebral function. The last decade, however, has brought a growing understanding that mitochondria play an even greater role than previously suspected. Increased understanding of the role of mitochondria in antioxidant defense and calcium homeostasis further solidified the importance of mitochondria in CNS function--just as increased understanding of mitochondrial roles in calcium-mediated toxicity and production of reactive species further exemplified the Janus role of mitochondria--as mediators of CNS dysfunction. Perhaps most unexpected, however, was the evidence that mitochondria serve as the dominant integrators, checkpoints, and amplifiers of the cell death signals in the CNS. The mechanism of propagation of cell death cascades by mitochondria remains controversial. In this review, we focus on the evidence that supports the involvement of an event termed the mitochondrial permeability transition that (i) occurs (patho)physiologically; (ii) occurs in the CNS, and; (iii) is a potential target for pharmaceutical intervention against CNS dysfunction, injury, and cell loss resulting from stroke, trauma, and neurodegenerative disease.     

Is there anything "autonomous" in the nervous system?

The terms "autonomous" or "vegetative" are currently used to identify one part of the nervous system composed of sympathetic, parasympathetic, and gastrointestinal divisions. However, the concepts that are under the literal meaning of these words can lead to misconceptions about the actual nervous organization. Some clear-cut examples indicate that no element shows "autonomy" in an integrated body. Nor are they solely "passive" or generated "without mental elaboration." In addition, to be "not consciously controlled" is not a unique attribute of these components. Another term that could be proposed is "homeostatic nervous system" for providing conditions to the execution of behaviors and maintenance of the internal milieu within normal ranges. But, not all homeostatic conditions are under the direct influence of these groups of neurons, and some situations clearly impose different ranges for some variables that are adaptative (or hazardous) in the tentative of successfully coping with challenging situations. Finally, the name "nervous system for visceral control" emerges as another possibility. Unfortunately, it is not only "viscera" that represent end targets for this specific innervation. Therefore, it is commented that no quite adequate term for the sympathetic, parasympathetic, and gastrointestinal divisions has already been coined. The basic condition for a new term is that it should clearly imply the whole integrated and collaborative functions that the components have in an indivisible organism, including the neuroendocrine, immunological, and respiratory systems. Until that, we can call these parts simply by their own names and avoid terms that are more "convenient" than appropriate.     

When and how does cell division order influence cell allocation to the inner cell mass of the mouse blastocyst?

Aggregate 8-cell embryos were constructed from four 2/8 pairs of blastomeres, one of which was marked with a short-term cell lineage marker and was also either 4 h older (derived from an early-dividing 4-cell) or 4 h younger (derived from a late-dividing 4-cell) than the other three pairs. The aggregate embryos were cultured to the 16-cell stage, at which time a second marker was used to label the outside cell population. The embryos were then disaggregated and each cell was examined to determine its labelling pattern. From this analysis, we calculated the relative contributions to the inside cell population of the 16-cell embryo of older and younger cells. Older cells were found to contribute preferentially. However, if the construction of the aggregate 8-cell embryo was delayed until each of the contributing 2/8 cell pairs had undergone intercellular flattening and then had been exposed to medium low in calcium to reverse this flattening immediately prior to aggregation, the advantage possessed by the older cells was lost. These results support the suggestion that older cells derived from early-dividing 4-cell blastomeres contribute preferentially to the inner cell mass as a result of being early-flattening cells.     

The influence of β-glucan on the growth and cell wall architecture of Aspergillus spp

β-1,3-glucan is a major component of fungal cell walls with various biological activities, including effects on the production of inflammatory mediators in vivo and in vitro. However, few reports have examined its influence on the fungal cell itself. In this study, the influences of β-1,3-glucan on the growth and cell wall structure of fungi was examined. Aspergillus fumigatus was cultured with a synthetic medium, C-limiting medium, in the presence or absence of β-1,3-glucan. Hyphal growth was promoted in liquid and solid-cultures by adding β-1,3-glucan. Glucose and dextran did not induce growth. The influence on cell wall structure of the β-glucan-added cultures was examined by enzymolysis and NMR spectroscopy and the amount of β-1,3-glucan found to be changed. β-1,3-glucan has been widely detected in the environment. In this study, it was demonstrated that β-1,3-glucan causes promotion of the growth, and a change in the cell wall architecture, of Aspergillus. Unregulated distribution of β-1,3-glucan would be strongly related to the incidence of infectious diseases and allergy caused by Aspergillus spp.     

Do inducers of apoptosis trigger caspase-independent cell death?

Apoptotic cell death is mediated by molecular pathways that culminate in the activation of a family of cysteine proteases, known as the caspases, which orchestrate the dismantling and clearance of the dying cell. However, mounting evidence indicates that a cell that has been treated with an apoptotic inducer can also initiate a suicide programme that does not rely on caspase activation. Here, we present recent findings and discuss the physiological relevance of caspase-independent cell death.     

Which cell death modality wins the contest for photodynamic therapy of cancer?

Photodynamic therapy (PDT) was discovered more than 100 years ago. Since then, many protocols and agents for PDT have been proposed for the treatment of several types of cancer. Traditionally, cell death induced by PDT was categorized into three types: apoptosis, cell death associated with autophagy, and necrosis. However, with the discovery of several other regulated cell death modalities in recent years, it has become clear that this is a rather simple understanding of the mechanisms of action of PDT. New observations revealed that cancer cells exposed to PDT can pass through various non-conventional cell death pathways, such as paraptosis, parthanatos, mitotic catastrophe, pyroptosis, necroptosis, and ferroptosis. Nowadays, immunogenic cell death (ICD) has become one of the most promising ways to eradicate tumor cells by activation of the T-cell adaptive immune response and induction of long-term immunological memory. ICD can be triggered by many anti-cancer treatment methods, including PDT. In this review, we critically discuss recent findings on the non-conventional cell death mechanisms triggered by PDT. Next, we emphasize the role and contribution of ICD in these PDT-induced non-conventional cell death modalities. Finally, we discuss the obstacles and propose several areas of research that will help to overcome these challenges and lead to the development of highly effective anti-cancer therapy based on PDT.Subject terms: Cancer immunotherapy, Cell death and immune response