The multifaceted role of glial cells in amyotrophic lateral sclerosis

Despite indisputable progress in the molecular and genetic aspects of amyotrophic lateral sclerosis (ALS), a mechanistic comprehension of the neurodegenerative processes typical of this disorder is still missing and no effective cures to halt the progression of this pathology have yet been developed. Therefore, it seems that a substantial improvement of the outcome of ALS treatments may depend on a better understanding of the molecular mechanisms underlying neuronal pathology and survival as well as on the establishment of novel etiological therapeutic strategies. Noteworthy, a convergence of recent data from multiple studies suggests that, in cellular and animal models of ALS, a complex pathological interplay subsists between motor neurons and their non-neuronal neighbours, particularly glial cells. These observations not only have drawn attention to the physiopathological changes glial cells undergo during ALS progression, but they have moved the focus of the investigations from intrinsic defects and weakening of motor neurons to glia–neuron interactions. In this review, we summarize the growing body of evidence supporting the concept that different glial populations are critically involved in the dreadful chain of events leading to motor neuron sufferance and death in various forms of ALS. The outlined observations strongly suggest that glial cells can be the targets for novel therapeutic interventions in ALS.     

Reverse transendothelial cell migration in inflammation: to help or to hinder?

The endothelium provides a strong barrier separating circulating blood from tissue. It also provides a significant challenge for immune cells in the bloodstream to access potential sites of infection. To mount an effective immune response, leukocytes traverse the endothelial layer in a process known as transendothelial migration. Decades of work have allowed dissection of the mechanisms through which immune cells gain access into peripheral tissues, and subsequently to inflammatory foci. However, an often under-appreciated or potentially ignored question is whether transmigrated leukocytes can leave these inflammatory sites, and perhaps even return across the endothelium and re-enter circulation. Although evidence has existed to support “reverse” transendothelial migration for a number of years, it is only recently that mechanisms associated with this process have been described. Here we review the evidence that supports both reverse transendothelial migration and reverse interstitial migration within tissues, with particular emphasis on some of the more recent studies that finally hint at potential mechanisms. Additionally, we postulate the biological significance of retrograde migration, and whether it serves as an additional mechanism to limit pathology, or provides a basis for the dissemination of systemic inflammation.     

Protective effect of lidocaine in the experimental foot-and-mouth disease pancreatitis

Experimental infection of mice with foot-and-mouth disease virus (FMDV) induces a necrotizing pancreatitis of the exocrinar portion of the organ. The lesions are characterized by vascular congestion, edema and interstitial polymorphonuclear leukocyte (PMN) infiltrates. When infected mice were treated with different amounts of lidocaine (a local anesthetic, chemically defined as a tertiary amide compound), reduction in intensity of the pancreatic necrosis and in the number of PMN were observed. Even though lidocaine could interfere with FMDV post-replicative cytolytic mechanisms, it appears that protection against pancreatic necrosis is by attenuation of PMN presentation in the infected tissue.     

The potential importance of myeloid-derived suppressor cells (MDSCs) in the pathogenesis of Alzheimer’s disease

The exact cause of Alzheimer’s disease (AD) is still unknown, but the deposition of amyloid-β (Aβ) plaques and chronic inflammation indicates that immune disturbances are involved in AD pathogenesis. Recent genetic studies have revealed that many candidate genes are expressed in both microglia and myeloid cells which infiltrate into the AD brains. Invading myeloid cells controls the functions of resident microglia in pathological conditions, such as AD pathology. AD is a neurologic disease with inflammatory component where the immune system is not able to eliminate the perpetrator, while, concurrently, it should prevent neuronal injuries induced by inflammation. Recent studies have indicated that AD brains are an immunosuppressive microenvironment, e.g., microglial cells are hyporesponsive to Aβ deposits and anti-inflammatory cytokines enhance Aβ deposition. Immunosuppression is a common element in pathological disorders involving chronic inflammation. Studies on cancer-associated inflammation have demonstrated that myeloid-derived suppressor cells (MDSCs) have a crucial role in the immune escape of tumor cells. Immunosuppression is not limited to tumors, since MDSCs can be recruited into chronically inflamed tissues where inflammatory mediators enhance the proliferation and activation of MDSCs. AD brains express a range of chemokines and cytokines which could recruit and expand MDSCs in inflamed AD brains and thus generate an immunosuppressive microenvironment. Several neuroinflammatory disorders, e.g., the early phase of AD pathology, have been associated with an increase in the level of circulating MDSCs. We will elucidate the immunosuppressive armament of MDSCs and present evidences in support of the crucial role of MDSCs in the pathogenesis of AD.     

Periostin in kidney diseases

Chronic kidney disease is an incurable to date pathology, with renal replacement therapy through dialysis or transplantation being the only available option for end-stage patients. A deeper understanding of the molecular mechanisms governing the progression of kidney diseases will permit the identification of unknown mediators and potential novel markers or targets of therapy which promise more efficient diagnostic and therapeutic applications. Over the last years, periostin was established by several studies as a novel key player in the progression of renal disease. Periostin is de novo expressed focally by the injured kidney cells during the development of renal disease. In diverse cohorts of renal disease patients, the expression levels of periostin in the kidney and urine were highly correlated with the stage of the pathology and the decline of renal function. Subsequent studies in animal models demonstrated that periostin is centrally involved in mediating renal inflammation and fibrosis, contributing to the deterioration of renal structure and function. Genetic or pharmaco-genetic inhibition of periostin in animal models of renal disease was efficient in arresting the progression of the pathology. This review will summarize the recent advances on periostin in the field of kidney diseases and will discuss its utility of as a novel target of therapy for chronic kidney disease.     

Astrocytes in multiple sclerosis: A product of their environment

It has long been thought that astrocytes, like other glial cells, simply provide a support mechanism for neuronal function in the healthy and inflamed central nervous system (CNS). However, recent evidence suggests that astrocytes play an active and dual role in CNS inflammatory diseases such as multiple sclerosis (MS). Astrocytes not only have the ability to enhance immune responses and inhibit myelin repair, but they can also be protective and limit CNS inflammation while supporting oligodendrocyte and axonal regeneration. The particular impact of these cells on the pathogenesis and repair of an inflammatory demyelinating process is dependent upon a number of factors, including the stage of the disease, the type and microenvironment of the lesion, and the interactions with other cell types and factors that influence their activation. In this review, we summarize recent data supporting the idea that astrocytes play a complex role in the regulation of CNS autoimmunity.     

Genetic susceptibility to hypertensive renal disease

Hypertensive renal disease occurs at increased frequency among the relatives of patients with this disease compared to individuals who lack a family history of disease. This suggests a heritable risk in which genetic variation may play a role. These observations have motivated a search for genetic variation contributing to this risk in both experimental animal models and in human populations. Studies of animal models indicate the capacity of natural genetic variants to contribute to disease risk and have produced a few insights into the disease mechanism. In its current phase, human population genetic studies have sought to associate genetic variation with disease in large populations by testing genotypes at a large number of common genetic variations in the genome, expecting that common genetic variants contributing to renal disease risk will be identified. These genome-wide association studies (GWAS) have been productive and are a clear technical success; they have also identified narrowly defined loci and genes containing variation contributing to disease risk. Further extension and refinement of these GWAS are likely to extend this success. However, it is also clear that few additional variants with substantial effects accounting for the greatest part of heritability will be uncovered by GWAS. This raises an interesting biological question regarding where the remaining unaccounted heritable risk may be located. At present, much consideration is being given to this question and to the challenge of testing hypotheses that lead from the various alternative mechanisms under consideration. One result of the progress of GWAS is likely to be a renewed interest in mechanisms by which related individuals can share and transmit traits independently of Mendelian inheritance. This paper reviews the current progress in this area and considers other mechanisms by which familial aggregation of risk for renal disease may arise.     

The buzz on caffeine in invertebrates: effects on behavior and molecular mechanisms

A number of recent studies from as diverse fields as plant–pollinator interactions, analyses of caffeine as an environmental pollutant, and the ability of caffeine to provide protection against neurodegenerative diseases have generated interest in understanding the actions of caffeine in invertebrates. This review summarizes what is currently known about the effects of caffeine on behavior and its molecular mechanisms in invertebrates. Caffeine appears to have similar effects on locomotion and sleep in both invertebrates and mammals. Furthermore, as in mammals, caffeine appears to have complex effects on learning and memory. However, the underlying mechanisms for these effects may differ between invertebrates and vertebrates. While caffeine’s ability to cause release of intracellular calcium stores via ryanodine receptors and its actions as a phosphodiesterase inhibitor have been clearly established in invertebrates, its ability to interact with invertebrate adenosine receptors remains an important open question. Initial studies in insects and mollusks suggest an interaction between caffeine and the dopamine signaling pathway; more work needs to be done to understand the mechanisms by which caffeine influences signaling via biogenic amines. As of yet, little is known about whether other actions of caffeine in vertebrates, such as its effects on GABA_A and glycine receptors, are conserved. Furthermore, the pharmacokinetics of caffeine remains to be elucidated. Overall behavioral responses to caffeine appear to be conserved amongst organisms; however, we are just beginning to understand the mechanisms underlying its effects across animal phyla.     

P58IPK, a novel cochaperone containing tetratricopeptide repeats and a J-domain with oncogenic potential

Tetratricopeptide repeats (TPRs) are loosely conserved 34-amino acid sequence motifs that have been shown to function as scaffolding structures to mediate protein-protein interactions. TPRs have been identified in a number of proteins with diverse functions and cellular locations. Recent studies suggest that individual TPR motifs can confer specificity in promoting homotypic and/or heterotypic interactions, often in a mutually exclusive manner. These features are best exemplified by the P58IPK protein, an influenza virus-activated cellular inhibitor of the PKR protein kinase, whose different TPR motifs mediate interactions with distinct proteins. P58IPK, which possesses cochaperone and oncogenic properties, represents a unique class of TPR proteins containing a J-domain. Here we review recent progress on the structural and functional characterization of P58IPK, and discuss the possible mechanisms by which P58IPK modulates PKR and induces tumorigenesis in view of present knowledge of TPR proteins and molecular chaperones.     

Membrane functional organisation and dynamic of μ-opioid receptors

The activation and signalling activity of the membrane μ-opioid receptor (MOP-R) involve interactions among the receptor, G-proteins, effectors and many other membrane or cytosolic proteins. Decades of investigation have led to identification of the main biochemical processes, but the mechanisms governing the successive protein–protein interactions have yet to be established. We will need to unravel the dynamic membrane organisation of this complex and multifaceted molecular machinery if we are to understand these mechanisms. Here, we review and discuss advances in our understanding of the signalling mechanism of MOP-R resulting from biochemical or biophysical studies of the organisation of this receptor in the plasma membrane.     

Alzheimer’s disease and CADASIL are heritable,adult-onset dementias that both involve damaged small blood vessels

This essay explores an alternative pathway to Alzheimer’s dementia that focuses on damage to small blood vessels rather than late-stage toxic amyloid deposits as the primary pathogenic mechanism that leads to irreversible dementia. While the end-stage pathology of AD is well known, the pathogenic processes that lead to disease are often assumed to be due to toxic amyloid peptides that act on neurons, leading to neuronal dysfunction and eventually neuronal cell death. Speculations as to what initiates the pathogenic cascade have included toxic abeta peptide aggregates, oxidative damage, and inflammation, but none explain why neurons die. Recent high-resolution NMR studies of living patients show that lesions in white matter regions of the brain precede the appearance of amyloid deposits and are correlated with damaged small blood vessels. To appreciate the pathogenic potential of damaged small blood vessels in the brain, it is useful to consider the clinical course and the pathogenesis of CADASIL, a heritable arteriopathy that leads to damaged small blood vessels and irreversible dementia. CADASIL is strikingly similar to early onset AD in that it is caused by germ line mutations in NOTCH 3 that generate toxic protein aggregates similar to those attributed to mutant forms of the amyloid precursor protein and presenilin genes. Since NOTCH 3 mutants clearly damage small blood vessels of white matter regions of the brain that lead to dementia, we speculate that both forms of dementia may have a similar pathogenesis, which is to cause ischemic damage by blocking blood flow or by impeding the removal of toxic protein aggregates by retrograde vascular clearance mechanisms.     

Ubiquitin-proteasome system

The proteolytic active sites of the 26S proteasome are sequestered within the central chamber of its 20S catalytic core particle. Access to this chamber is through a narrow channel defined by the outer alpha subunits. Free proteasome 20S core particles are found in an autoinhibited state in which the N-termini of neighboring alpha subunits are anchored by an intricate lattice of interactions blocking access to the channel. Entry of substrates into proteasomes can be enhanced by attachment of activators or regulatory particles. An important part of this activation is channel gating; regulatory particles rearrange the blocking residues to form an open pore and promote substrate entry into the proteolytic chamber. Interestingly, some substrates can open the entrance themselves and thus facilitate their own destruction. In this review, we will discuss the mechanisms proposed for channel gating and the interactions required to maintain stable closed and open conformations.     

The persistence of T cell memory

T cell memory is a crucial feature of the adaptive immune system in the defense against pathogens. During the last years, numerous studies have focused their efforts on uncovering the signals, inflammatory cues, and extracellular factors that support memory differentiation. This research is beginning to decipher the complex gene network that controls memory programming. However, how the different signals, that a T cell receives during the process of differentiation, interplay to trigger memory programming is still poorly defined. In this review, we focus on the most recent advances in the field and discuss how T cell receptor signaling and inflammation control CD8 memory differentiation.     

Influence of atmospheric factors on the rheumatic diseases

There appears to be ample evidence to conclude that various meteorological factors do exert a significant impact on some people with various rheumatic diseases. The data is, however, crude relative to our general understanding. Most of this research on RA has dealt with the primary signs and symptoms of inflammation. We know, however, many of the chemical mediators of inflammation. It seems like a logical progression of research to determine the effects of the meteorological/atmospheric factors of concern on these specific intrinsic mediators of inflammation. In general, gout can be very well controlled through medication. The evidence suggests, however, that we may gain a much better understanding of how atmospheric factors such as temperature can effect the body through changes in its physico-chemical processes by using Gout as a model. The work with SLE has already yielded useful applications. Sun screening pharmaceuticals have been quite successful in reducing exacerbations of symptoms. But we don't know why only some people are photosensitive. The previous research on the effects of atmospheric factors on the rheumatic diseases has illustrated key issues in methodology: large sample sizes are critical, objective and quantifiable disease variables are important, the variables measured must be specific to the questions investigated, the diseases investigated must be as specifically and accurately defined as possible, and the various aspects of 'weather' to be investigated must be specifically defined and quantified. It is apparent that there is much more important and useful work to be performed before we can understand the effects of atmospheric factors on the rheumatic diseases.     

Sleeping sickness and the brain

Recent progress in understanding the neuro-pathological mechanisms of sleeping sickness reveals a complex relationship between the trypanosome parasite that causes this disease and the host nervous system. The pathology of late-stage sleeping sickness, in which the central nervous system is involved, is complicated and is associated with disturbances in the circadian rhythm of sleep. The blood-brain barrier, which separates circulating blood from the central nervous system, regulates the flow of materials to and from the brain. During the course of disease, the integrity of the blood-brain barrier is compromised. Dysfunction of the nervous system may be exacerbated by factors of trypanosomal origin or by host responses to parasites. Microscopic examination of cerebrospinal fluid remains the best way to confirm late-stage sleeping sickness, but this necessitates a risky lumbar puncture. Most drugs, including many trypanocides, do not cross the blood-brain barrier efficiently. Improved diagnostic and therapeutic approaches are thus urgently required. The latter might benefit from approaches which manipulate the blood-brain barrier to enhance permeability or to limit drug efflux. This review summarizes our current understanding of the neurological aspects of sleeping sickness, and envisages new research into blood-brain barrier models that are necessary to understand the interactions between trypanosomes and drugs active against them within the host nervous system. Received 10 October 2001; received after revision 29 November 2001; accepted 5 December 2001     

The role of synapsins in neuronal development

The synapsins, the first identified synaptic vesicle-specific proteins, are phosphorylated on multiple sites by a number of protein kinases and are involved in neurite outgrowth and synapse formation as well as in synaptic transmission. In mammals, the synapsin family consists of at least 10 isoforms encoded by 3 distinct genes and composed by a mosaic of conserved and variable domains. The synapsins are highly conserved evolutionarily, and orthologues have been found in invertebrates and lower vertebrates. Within nerve terminals, synapsins are implicated in multiple interactions with presynaptic proteins and the actin cytoskeleton. Via these interactions, synapsins control several mechanisms important for neuronal homeostasis. In this review, we describe the main functional features of the synapsins, in relation to the complex role played by these phosphoproteins in neuronal development.     

Expression and function of nuclear receptor co-activator 4: evidence of a potential role independent of co-activator activity

Nuclear receptor coactivator 4 (NcoA4), also known as androgen receptor-associated protein 70 (ARA70), was initially discovered as a component of Ret-Fused Gene expressed in a subset of papillary thyroid carcinomas. Subsequent studies have established NcoA4 as a coactivator for a variety of nuclear receptors, including peroxisome proliferator activated receptors α and γ, and receptors for steroid hormones, vitamins D and A, thyroid hormone, and aryl hydrocarbons. While human NcoA4 has both LXXLL and FXXLF motifs that mediate p160 coactivator nuclear receptor interactions, this ubiquitously expressed protein lacks clearly defined functional domains. Several studies indicate that NcoA4 localizes predominantly to the cytoplasm and affects ligand-binding specificity of the androgen receptor, which has important implications for androgen-independent prostate cancer. Two NcoA4 variants, which may exert differential activities, have been identified in humans. Recent studies suggest that NcoA4 may play a role in development, carcinogenesis, inflammation, erythrogenesis, and cell cycle progression that may be independent of its role as a receptor coactivator. This review summarizes what is currently known of the structure, expression, regulation, and potential functions of this unique protein in cancerous and non-cancerous pathologies.