Current Molecular Medicine (v.11, #1)
Converging Pathways in the Occurrence of Endoplasmic Reticulum (ER) Stress in Huntington's Disease by R. Vidal, B. Caballero, A. Couve, C. Hetz (1-12).
A variety of neurological diseases including Huntington's disease (HD), Alzheimer's disease and Parkinson's disease share common neuropathology, primarily featuring the presence of abnormal protein inclusions containing specific misfolded proteins. Mutations leading to expansion of a poly-glutamine track in Huntingtin cause HD, and trigger its misfolding and aggregation. Recent evidence indicates that alterations in the secretory pathway, in particular the endoplasmic reticulum (ER), are emerging features of HD. Although it is not clear how cytoplasmic/nuclear located mutant Huntingtin alters the function of the ER, several reports indicate that mutant Huntingtin affects many essential processes related to the secretory pathway, including inhibition of ER-associated degradation, altered ER/Golgi vesicular trafficking and axonal transport, disrupted autophagy and abnormal ER calcium homeostasis. All these alterations are predicted to have a common pathological outcome associated to disturbance of protein folding and maturation pathways at the ER, generating chronic ER stress and neuronal dysfunction. Here, we review recent evidence involving ER stress in HD pathogenesis and discuss possible therapeutic strategies to target organelle function in the context of disease.
Eicosanoids in Prevention and Management of Diseases by J. Szefel, M. Piotrowska, W. J. Kruszewski, J. Jankun, W. Lysiak-Szydlowska, E. Skrzypczak-Jankun (13-25).
Eicosanoids, which originate from polyunsaturated fatty acids (PUFAs), have a major impact on homeostasis maintenance as secondary signal transducers. Signal cascade, which includes reception, processing and signal transduction coming from the environment into the cell, determines the type of response evoked. Signal distortion may take place on every level of this cascade and this in consequence could lead to the development of many diseases. Any intervention into PUFAs metabolism leads to quantitative and qualitative changes of synthesized eicosanoids. Some of them promote, whereas others inhibit carcinogenesis, some are pro- or anti-inflammatory and the overall result depends on the outcome of these contradictory effects. The type and amount of produced eicosanoids depends on substrates' availability and activity of enzymes catalyzing different stages of their transformation. A particularly negative role was assigned to the over expression of phospholipase A2, cyclooxygenase-2, 5- and 12-lipoxygenases, while the contribution of other oxygenases and their metabolites is considerably less clear. The information about their interplay is extremely sparse and inadequate to understand intricacies of the mechanisms involved. There are indications that utilization of selected eicosanoids (their analogs, agonists or antagonists) could be a better way of disease prevention and treatment, more effective than excessive dietary supplementation of fatty acids. This review presents a more global picture of oxygenases and their PUFA metabolites giving a brief summary of our current understanding of perspectives and pitfalls of their regulation and mediatory action in human diseases.
The Dual Role of Interleukin-25 in the Control of Immune-Mediated Pathologies by R. Caruso, C. Stolfi, D. De Nitto, F. Pallone, G. Monteleone (26-30).
Interleukin-25 (IL-25) plays a key role in the initiation and expansion of T helper (Th) 2 cell-mediated immune responses, thereby contributing to allergic diseases and host defense against helminthic parasites. More recent studies have however shown that IL-25 can also control the function of non-T cells, such as antigen presenting cells and endothelial cells, and reduces Th1/Th17-mediated pathologies. These new and exciting observations reveal a broader role for IL-25 than previously anticipated, and delineate various scenarios where therapeutic interventions around IL-25 activity can be imagined.
The Molecular Machinery Regulating Apoptosis Signal Transduction and its Implication in Human Physiology and Pathophysiologies by C. T. Hellwig, E. Passante, M. Rehm (31-47).
The regulation of apoptotic cell death, a terminal and fatal cell fate decision, has been intensely investigated and, due to its paramount implications for human health and disease, has sparked one of the most prolific and competitive research fields in biological and biomedical sciences of the past decades. Many key components of the molecular machinery processing and transducing apoptotic cell death signals have been described in great detail by now, dramatically advancing our understanding of how the network of apoptosis signaling proteins integrates and regulates cell death signals, and ultimately executes apoptosis. Building on the latest significant advances in deciphering apoptosis signal transduction as well as on the central original groundbreaking discoveries in cell death research, we here present an in-depth description of the current knowledge on the core molecular machinery of apoptotic signaling and how it is implicated in human physiology and pathophysiologies.
Transforming Growth Factor-β Signaling in Motor Neuron Diseases by M. Katsuno, H. Adachi, H. Banno, K. Suzuki, F. Tanaka, G. Sobue (48-56).
Transforming growth factor and#946; (TGF-and#946;), a pleiotropic cytokine, regulates a diverse range of cellular responses, such as proliferation, differentiation, migration, and apoptosis. The TGF-and#946;1, -and#946;2, and -and#946;3 isoforms are expressed by neurons and glial cells, and their receptors are expressed throughout the central nervous system. Several lines of evidence demonstrate that TGF-and#946; signaling protects neurons from glutamate mediated excitotoxicity, a putative mechanism underlying the pathogenesis of various neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Recent studies indicate that the TGF-and#946;-Smad2/3 pathway restores motor function in a mouse model of ALS, and that disruption of TGF-and#946; signaling due to the transcriptional dysregulation of its receptor is associated with polyglutamine-induced motor neuron damage in spinal and bulbar muscular atrophy. Moreover, the TGF-and#946;-Smad2/3 pathway regulates the function of glial cells, although the implication of this regulation in neurodegeneration remains elusive. Conversely, myostatin, a member of the TGF-and#946; superfamily, has gained attention as a potential therapeutic target for neuromuscular disorders because genetic deletion of this factor results in increased muscle volume. Signal transduction by BMP, a member of the TGF-and#946; super family, regulates the function and growth of the neuromuscular junction, while the disruption of this signaling has been reported in animal models of hereditary spastic paraplegia. These findings support the hypothesis that the disruption of TGF-and#946; signaling is an important molecular event in the pathogenesis of motor neuron diseases, and that the modification of this signaling pathway represents a new therapeutic strategy against these devastating disorders.
Heterogeneity Amongst 5-HT3 Receptor Subunits: Is this Significant? by N. Yaakob, D. T. Malone, B. Exintaris, H. R. Irving (57-68).
The serotonin 3 (5-HT3) receptor is a ligand gated ion channel unlike the other 5-HT receptors which are G protein coupled receptors. The functional 5-HT3 receptor forms a pentamer of five symmetrically arranged subunits surrounding a central pore. The 5-HT3A subunit was first identified at a molecular level and can form functional homomers or heteromers with the 5-HT3B subunit. Recently, three new 5-HT3 subunits have been discovered and these can also form functional heteromers with the 5-HT3A subunit. In addition, splice variants of the 5-HT3 subunits have also been reported. These findings have markedly increased the complexity of the 5-HT3 receptor and may form part of the explanation of unresolved differences between studies investigating 5-HT3 receptor function in cell lines compared with native tissues. In this review we discuss the properties of the different subunits and their distribution to determine if they contribute to functional changes in the 5-HT3 receptor. Several recent pharmacogenomic studies have revealed single nucleotide polymorphisms (SNPs) and other variations in the different 5-HT3 receptor subunits that are associated with various clinical conditions. We discuss the implications of these findings with respect to drug design and tailored pharmacogenomic therapies.
Cancer Stem Cells Switch on Tumor Neovascularization by Y.-F. Ping, X.-W. Bian (69-75).
Recent studies on cancer stem cells (CSCs), a special subpopulation of tumor cells, promote our understanding of tumorigenesis, neovascularization, invasion, drug resistance and tumor recurrence, which establishes new concepts for cancer diagnosis and treatment. Therefore, the biological features and behaviors of CSCs have become an exciting frontier of cancer research. CSCs initiate tumor neovascularization and promote invasion with yet to be defined mechanisms. In this review, we provide evidence for the role of CSCs in tumor vascularization and discuss the potential mechanisms and therapeutic significance based on the interaction between CSCs and their vascular niches.