Band 4, Heft 5

Epigenetic processes, such as DNA methylation and histone acetylation, regulate the genome-environment interactions that may play important roles in a wide range of brain disorders, including Alzheimer’s disease (AD). Indeed, the role of epigenetic machinery in learning and memory processes is well documented. In this review, we will focus on the most recent literature on tools that target epigenetic mechanisms, particularly on histone acetylation, and we will discuss the use of chemical probes to validate these targets in therapeutic strategies for AD.

Nuclear distribution element 1 (NDE1, also known as NudE) and NDE-like 1 (NDEL1, also known as Nudel) are paralogous proteins essential for mitosis and neurodevelopment that have been implicated in psychiatric and neurodevelopmental disorders. The two proteins possess high sequence similarity and have been shown to physically interact with one another. Numerous lines of experimental evidence in vivo and in cell culture have demonstrated that these proteins share common functions, although instances of differing functions between the two have recently emerged. We review the key aspects of NDE1 and NDEL1 in terms of recent advances in structure elucidation and cellular function, with an emphasis on their differing mechanisms of post-translational modification. Based on a review of the literature and bioinformatics assessment, we advance the concept that the twin proteins NDE1 and NDEL1, while sharing a similar ‘nature’ in terms of their structure and basic functions, appear to be different in their ‘nurture’, the manner in which they are regulated both in terms of expression and of post-translational modification within the cell. These differences are likely to be of significant importance in understanding the specific roles of NDE1 and NDEL1 in neurodevelopment and disease.

Along the entire lifetime, Notch is actively involved in dynamic changes in the cellular architecture and function of the nervous system. It controls neurogenesis, the growth of axons and dendrites, synaptic plasticity, and ultimately neuronal death. The specific roles of Notch in adult brain plasticity and neurological disorders have begun to be unraveled in recent years, and pieces of experimental evidence suggest that Notch is operative in diverse brain pathologies including tumorigenesis, stroke, and neurological disorders such as Alzheimer’s disease, Down syndrome, and multiple sclerosis. In this review, we will cover the recent findings of Notch signaling and neural dysfunction in adult human brain and discuss its relevance in the pathogenesis of diseases of the central nervous system.

The animal body is composed of a variety of cells and extracellular matrices that are organized and orchestrated in a harmonized manner to support life. Therefore, the critical importance of a comprehensive understanding of the molecular network surrounding and integrating the cells is now emphasized. The CCN family is a novel group of matricellular proteins that interact with and orchestrate a number of extracellular signaling and matrix molecules to construct and maintain living tissues. This family comprises six distinct members in mammals, which are characterized by a unique and conserved modular structure. These proteins are not targeted to limited and specific receptors to execute specific missions, but manipulate a vast number of biomolecules in the network by serving as a molecular hub at the center. The unified nomenclature, CCN, originates from a simple acronym of the three classical members, which helps us to avoid having any preconception about their pleiotropic and anonymous functional nature. In this review, after a brief summary of the general molecular concepts regarding the CCN family, new aspects of each member uncovered by recent research are introduced, which represent, nevertheless, only the tip of the iceberg of the profound functionality of these molecules.

Bovine lactoferricin (LfcinB) is a multifunctional peptide derived from bovine lactoferrin that demonstrates antibacterial, antifungal, antiviral, antitumor, and immunomodulatory activities. Recently, studies have focused on the anti-catabolic and anti-inflammatory potential of LfcinB. LfcinB is able to modulate the effects cytokines such as IL-1 and fibroblast growth factor 2 as well as promote specific cartilage anabolic factors. These properties are particularly important in maintaining cartilage homeostasis and preventing a catabolic state, which leads to clinical pathology. This review focuses on the recent literature elucidating the role of LfcinB in preventing cartilage degradation.

Low-density lipoproteins (LDLs, also known as ‘bad cholesterol’) are the major carriers of circulating cholesterol and the main causative risk factor of atherosclerosis. Plasma LDLs are 20- to 25-nm nanoparticles containing a core of cholesterol esters surrounded by a phospholipid monolayer and a single copy of apolipoprotein B (550 kDa). An early sign of atherosclerosis is the accumulation of LDL-derived lipid droplets in the arterial wall. According to the widely accepted ‘response-to-retention hypothesis’, LDL binding to the extracellular matrix proteoglycans in the arterial intima induces hydrolytic and oxidative modifications that promote LDL aggregation and fusion. This enhances LDL uptake by the arterial macrophages and triggers a cascade of pathogenic responses that culminate in the development of atherosclerotic lesions. Hence, LDL aggregation, fusion, and lipid droplet formation are important early steps in atherogenesis. In vitro , a variety of enzymatic and nonenzymatic modifications of LDL can induce these reactions and thereby provide useful models for their detailed analysis. Here, we summarize current knowledge of the in vivo and in vitro modifications of LDLs leading to their aggregation, fusion, and lipid droplet formation; outline the techniques used to study these reactions; and propose a molecular mechanism that underlies these pro-atherogenic processes. Such knowledge is essential in identifying endogenous and exogenous factors that can promote or prevent LDL aggregation and fusion in vivo and to help establish new potential therapeutic targets to decelerate or even block these pathogenic reactions.

CAP superfamily proteins, also known as sperm-coating proteins, are found in all kingdoms of life and have been implicated in a variety of physiological contexts, including immune defense in plants and mammals, sperm maturation and fertilization, fungal virulence, and toxicity of insect and reptile venoms as well as prostate and brain cancer. CAP family members are mostly secreted glycoproteins that are highly stable in the extracellular fluid. All members of the superfamily share a common CAP domain of approximately 150 amino acids, which adopts a unique α-β-α sandwich fold. The conserved structure suggests that CAP proteins exert fundamentally similar functions. However, the molecular mode of action of this protein family has remained enigmatic. The budding yeast Saccharomyces cerevisiae has three CAP family members designated Pry (pathogen related in yeast), and recent evidence indicates that they act as sterol-binding and export proteins. Expression of the mammalian CAP protein CRISP2, which binds sterols in vitro , complements the sterol export defect of a yeast pry mutant, suggesting that sterol binding and export is conserved among different CAP family members. Collectively, these observations suggest that CAP family members constitute a novel class of secreted extracellular sterol-binding proteins. A ligand-binding activity of the CAP domain could explain many of the biological activities attributed to these proteins. For example, the strong induction of plant pathogenesis-related 1 protein upon exposure to pathogens may serve to inhibit pathogen proliferation by extracting sterols from the pathogen membrane. Similarly, the presence of these proteins in the venom of toxic insects and reptiles or in the secretome of pathogenic fungi might inflict damage by sequestering sterols or related small hydrophobic compounds from the host tissue.

Plant phospholipase As (PLAs) are a complex group of enzymes that catalyze the release of free fatty acids from phospholipids. Plant PLAs can be grouped into three families, PLA 1 , PLA 2 , and patatin-like PLA, that catalyze the hydrolysis of acyl groups from the sn-1 and/or sn-2 position. Each family is composed of multiple isoforms of phospholipases that differ in structural, catalytic, and physiological characteristics. In this review, recently acquired information on molecular, biochemical, and functional aspects of plant PLAs will be discussed.

Methicillin-resistant Staphylococcus aureus (MRSA) is the most frequent cause of hospital-associated morbidity and mortality. One reason why MRSA has remained a serious threat to public health is that new clones of MRSA constantly keep re-emerging. These new clones are better adapted to thrive in the hospital environment or even the community than their predecessors because they have developed increased and diversified antibiotic resistance and/or enhanced virulence. In addition, non-symptomatic colonization has been identified as a risk factor for subsequent MRSA infection; therefore, acquisition of factors promoting colonization has gained increased attention regarding the surge of MRSA outbreak clones. Two specific genes or genetic loci, namely sasX and the arginine catabolic mobile element (ACME), could recently be linked to the epidemiological success of MRSA clones, supporting the notion that colonization factors play a crucial role in MRSA outbreaks. SasX is a surface protein that enhances nasal colonization. ACME contains an arc arginine deiminase gene cluster promoting the survival of MRSA in the acidic skin environment, in addition to a polyamine resistance gene that deals with the increased production of toxic polyamines by the host that is prompted by arc . Notably, a better understanding of MRSA colonization on the molecular level may lead to eradication strategies based on vaccination or bacterial interference, with great promise to decrease MRSA infection rates.