Glutamate and Parkinson’s disease

Altered glutamatergic neurotransmission and neuronal metabolic dysfunction appear to be central to the pathophysiology of Parkinson’s disease (PD). The substantia nigra pars compacta—the area where the primary pathological lesion is located—is particularly exposed to oxidative stress and toxic and metabolic insults. A reduced capacity to cope with metabolic demands, possibly related to impaired mitochondrial function, may render nigral neurons highly vulnerable to the effects of glutamate, which acts as a neurotoxin in the presence of impaired cellular energy metabolism. In this way, glutamate may participate in the pathogenesis of PD. Degeneration of dopamine nigral neurons is followed by striatal dopaminergic denervation, which causes a cascade of functional modifications in the activity of basal ganglia nuclei. As an excitatory neurotransmitter, glutamate plays a pivotal role in normal basal ganglia circuitry. With nigrostriatal dopaminergic depletion, the glutamatergic projections from subthalamic nucleus to the basal ganglia output nuclei become overactive and there are regulatory changes in glutamate receptors in these regions. There is also evidence of increased glutamatergic activity in the striatum. In animal models, blockade of glutamate receptors ameliorates the motor manifestations of PD. Therefore, it appears that abnormal patterns of glutamatergic neurotransmission are important in the symptoms of PD. The involvement of the glutamatergic system in the pathogenesis and symptomatology of PD provides potential new targets for therapeutic intervention in this neuro-degenerative disorder.     

Α-synuclein misfolding and Parkinson's disease

Substantial evidence links α-synuclein, a small highly conserved presynaptic protein with unknown function, to both familial and sporadic Parkinson's disease (PD). α-Synuclein has been identified as the major component of Lewy bodies and Lewy neurites, the characteristic proteinaceous deposits that are the hallmarks of PD. α-Synuclein is a typical intrinsically disordered protein, but can adopt a number of different conformational states depending on conditions and cofactors. These include the helical membrane-bound form, a partially-folded state that is a key intermediate in aggregation and fibrillation, various oligomeric species, and fibrillar and amorphous aggregates. The molecular basis of PD appears to be tightly coupled to the aggregation of α-synuclein and the factors that affect its conformation. This review examines the different aggregation states of α-synuclein, the molecular mechanism of its aggregation, and the influence of environmental and genetic factors on this process.     

Selenium and Behçet's disease

Behçet's disease is an inflammatory disorder of unknown etiology, characterized by recurrent oral and genital aphthous ulcers, ocular inflammation, and skin lesions of erythema nodusum and acneiformeruptions. Selenium (Se) affects all components of the immune system, i.e., the development and expression of nonspecific, humoral, and cell-mediated responses. In general, a deficiency in Se appears to result in immunosuppression, whereas supplementation with low doses of Se appears to result in augmentation and/or restoration of immunoglogic functions. In this study, the distribution of Se and IgG, IgM in serum were compared in samples from healthy adult control and Behçet's disease patients. The serum Se levels were measured by AA-30-40 Varian Spectra, and immunoglobulins were measured by immunodiffusion technique. The mean (SD) serum Se level of 54.24 ± 8.06 ng/mL among Behçet's disease subjects was significantly different (P<0.01) from that in the control subjects (90.01 ± 9.94 ng/mL). We also measured IgG and IgM as 10.01 ± 2.74 mg/mL and 1.26 ± 0.29 mg/mL, respectively for patients, and 15.08 ± 4.73 mg/mL and 1.58 ± 0.43 mg/mL for controls. The mean values of IgG and IgM for patients were significantly (P<0.05) different from the values of controls. It seems, therefore, that a deficiency in selenium impedes the humoral immune response.     

α-Synuclein misfolding and Parkinson's disease

Substantial evidence links α-synuclein, a small highly conserved presynaptic protein with unknown function, to both familial and sporadic Parkinson's disease (PD). α-Synuclein has been identified as the major component of Lewy bodies and Lewy neurites, the characteristic proteinaceous deposits that are the hallmarks of PD. α-Synuclein is a typical intrinsically disordered protein, but can adopt a number of different conformational states depending on conditions and cofactors. These include the helical membrane-bound form, a partially-folded state that is a key intermediate in aggregation and fibrillation, various oligomeric species, and fibrillar and amorphous aggregates. The molecular basis of PD appears to be tightly coupled to the aggregation of α-synuclein and the factors that affect its conformation. This review examines the different aggregation states of α-synuclein, the molecular mechanism of its aggregation, and the influence of environmental and genetic factors on this process.     

Amyloid β protein and Alzheimer disease

Amyloid beta protein is predominant in senile plaques, the neuropathologic hallmarks of Alzheimer disease. Researchers in Winnipeg have shown that this protein can overstimulate certain hydrolytic enzymes to break down the phospholipid building blocks of the brain-cell wall. They speculate that the abnormal destruction of phospholipids gradually drains the energy resources a neuron uses to rebuild its membrane. As neurons "burn out," the brain loses its ability to function normally. In view of evidence that NSAID therapy may interfere with the hydrolysis of phospholipids, the researchers will focus on finding an NSAID-related compound effective against Alzheimer disease.     

Axon-glial disruption: the link between vascular disease and Alzheimer's disease?

Vascular risk factors play a critical role in the development of cognitive decline and AD (Alzheimer's disease), during aging, and often result in chronic cerebral hypoperfusion. The neurobiological link between hypoperfusion and cognitive decline is not yet defined, but is proposed to involve damage to the brain's white matter. In a newly developed mouse model, hypoperfusion, in isolation, produces a slowly developing and diffuse damage to myelinated axons, which is widespread in the brain, and is associated with a selective impairment in working memory. Cerebral hypoperfusion, an early event in AD, has also been shown to be associated with white matter damage and notably an accumulation of amyloid. The present review highlights some of the published data linking white matter disruption to aging and AD as a result of vascular dysfunction. A model is proposed by which chronic cerebral hypoperfusion, as a result of vascular factors, results in both the generation and accumulation of amyloid and injury to white matter integrity, resulting in cognitive impairment. The generation of amyloid and accumulation in the vasculature may act to perpetuate further vascular dysfunction and accelerate white matter pathology, and as a consequence grey matter pathology and cognitive decline.     

Wnt/β-catenin signaling and disease

The WNT signal transduction cascade controls myriad biological phenomena throughout development and adult life of all animals. In parallel, aberrant Wnt signaling underlies a wide range of pathologies in humans. In this Review, we provide an update of the core Wnt/β-catenin signaling pathway, discuss how its various components contribute to disease, and pose outstanding questions to be addressed in the future.     

Alzheimer’s disease and gut microbiota

Alzheimer’s disease (AD) is a most common neurodegenerative disorder, which associates with impaired cognition. Gut microbiota can modulate host brain function and behavior via microbiota-gut-brain axis, including cognitive behavior. Germ-free animals, antibiotics, probiotics intervention and diet can induce alterations of gut microbiota and gut physiology and also host cognitive behavior, increasing or decreasing risks of AD. The increased permeability of intestine and blood-brain barrier induced by gut microbiota disturbance will increase the incidence of neurodegeneration disorders. Gut microbial metabolites and their effects on host neurochemical changes may increase or decrease the risk of AD. Pathogenic microbes infection will also increase the risk of AD, and meanwhile, the onset of AD support the “hygiene hypothesis”. All the results suggest that AD may begin in the gut, and is closely related to the imbalance of gut microbiota. Modulation of gut microbiota through personalized diet or beneficial microbiota intervention will probably become a new treatment for AD.     

Periodontal disease,Porphyromonas gingivalis,and rheumatoid arthritis: what triggers autoimmunity and clinical disease?

Rheumatoid arthritis, currently regarded as a complex multifactorial disease, was initially characterized as such at the turn of the 19th century. Ever since, multiple lines of investigation have attempted to elucidate the etiological factor(s) involved in disease incidence. Genes – including those risk alleles within HLA-DR4 – have been implicated but are insufficient to explain the vast majority of cases. Several environmental factors, therefore, are being studied. Among them, the role of periodontal disease and Porphyromonas gingivalis in the pathogenesis of rheumatoid arthritis has attracted both clinical and bench interest given supportive epidemiologic and mechanistic data.The notion that rheumatoid arthritis (RA) is a polygenic autoimmune disorder that requires environmental factors in order to become clinically apparent is not novel. Since the very beginning, infectious agents have been implicated. This includes early theories such as the ‘oral sepsis’ hypothesis, which supported the notion that periodontal infections were the true etiologic factors behind many chronic diseases. Soon after, dental extraction became a central part of the RA therapeutic armamentarium.Over the last decade, an ever-increasing body of literature has been devoted to study the association between periodontal disease, Porphyromonas gingivalis, and RA. In this issue of Arthritis Research & Therapy, Arvikar and colleagues [1] demonstrate a positive correlation between P. ginigivalis antibody responses and presence/levels of anti-cyclic citrullinated peptide antibodies in a subset of patients with early RA. Moreover, subjects with serological reactivity toward P. ginvgivalis also tended to have higher RA disease activity as measured by Disease Activity Score in 28 Joints and Clinical Disease Activity Index. This occurred both at baseline – that is, in recently diagnosed patients who have not previously been treated with disease-modifying anti-rheumatic drugs (DMARDs) – and 12 months after initiation of therapy.The study had several strengths. First, the authors enrolled early RA patients who were DMARD-naïve at the time of antibody measurements and clinical assessments. Second, patients were followed for a period of 1 year to address biologic and phenotypic alterations after initiation of therapy. This is of utmost importance since very few studies have addressed clinical and immunologic changes at the very onset of disease [2,3]. Too often, however, the natural history of RA is studied without considering the confounding effects of long-standing systemic inflammation or immunosuppressive therapies or both. It is almost certain that the use of DMARDs and biologics alters the quantification and behavior of multiple immune cells and proteins (including auto- and alloantibody responses), thus distorting the true understanding of disease pathogenesis. Efforts to elucidate the earliest changes in pre-clinical and clinical RA are underway [2,4].An accumulating body of evidence suggests a role for clinical periodontal diseases in RA pathogenesis. Periodontitis was more common and severe in patients with RA compared with osteoarthritis [5], and subjects with RA had an increased likelihood of periodontitis compared with controls [6]. Multiple recent studies have specifically implicated P. gingivalis, a periodontopathic bacterium, as a possible triggering factor. This microorganism has gained scientific attention given its ability to citrullinate peptides via unique enzymatic properties conferred by peptydil arginine deiminase (PAD), which reportedly promotes the generation of neoantigens and the subsequent production of antibodies to citrullinated protein antigens (ACPAs). Experimentally, P. gingivalis-PAD is capable of citrullinating human peptides [7] and ACPAs have proven pathogenic in murine models of arthritis [8].A decade ago, it was postulated that a specific humoral immune response to P. gingivalis was the actual stimulus for the development of RA [9]. Since then, multiple reports used serological methods [10,11] to correlate the generation of antibodies to P. gingivalis with autoimmunity (that is, ACPA antibodies) and clinical RA. Several lessons can be learned from these types of approaches. First, as in the case of reports by Arvikar and colleagues [1] and others [2,10,11], the methodology and antigens used to quantify anti-P. gingivalis antibodies have been heterogeneous. Prior studies used antibodies against whole-cell, bacterial lipopolysaccharide, or P. gingivalis-specific chaperone protein. The sensitivity and specificity of each one of these antibodies (and their measurements through different phases of disease) add to the complexity of correlating P. gingivalis serologic responses to RA pathogenesis. A concerted effort toward standardization is warranted in the interest of scientific validation and replication. Second, very few studies have reported the direct presence of P. gingivalis (or other periodontopathic bacteria) in subgingival biofilms of patients with RA. This can now be achieved without the need for laborious, classic microbiologic culture techniques. The advent of high-throughput, bacterial DNA sequencing has allowed taxonomic classification of multiple bacterial species within hundreds of samples (that is, microbiome analysis) in a matter of days.Finally, and perhaps more importantly, virtually all studies consistently reported only a small fraction of RA patients as being exposed to P. gingivalis (serologically, microbiologically, or both). This can have several (and possibly complementary) explanations. It is conceivable that the overabundance of other, non-measured, periodontopathic bacteria (or the lack of protective flora or both) contributes to disease initiation. Moreover, exposure to bacterial antigenic burden at other body sites, such as the lung or the gut, may represent triggering factors for RA. The intestinal microbiome, for example, is vast and diverse. It contains 100 times more protein-coding genes than the human genome and harbors 100 trillion cells (10-fold the amount of total host human cells). Studies in animal models support the notion that the oral, lung, or intestinal microbiome (or a combination thereof) is required to develop inflammatory arthritis. This is based on the fact that rodents do not develop joint inflammation under germ-free conditions or when treated with antibiotics. It is plausible, therefore, that an alteration in the bacterial taxa of several mucosal sites (including oral, lung, and intestinal microbiomes) is required for the transition from a pre-clinical, autoimmune phase of RA into clinically classifiable disease.Novel and comprehensive approaches for the study of the microbiome and the initiation of RA are now possible. Immunologic and microbiome analyses in prospective cohorts of subjects with periodontal disease and other risk factors for the development of RA (for example, first-degree relatives, discordant twins, or asymptomatic individuals with circulating autoantibodies or a combination thereof) may help elucidate some of these questions and ultimately target these organisms (or their components) as a diagnostic or even preventive strategy for RA.     

Copper transport and Alzheimer’s disease

This brief review discusses copper transport in humans, with an emphasis on knowledge learned from one of the simplest model organisms, yeast. There is a further focus on copper transport in Alzheimer’s Disease (AD). Copper homeostasis is essential for the well-being of all organisms, from bacteria to yeast to humans: survival depends on maintaining the required supply of copper for the many enzymes, dependent on copper for activity, while ensuring that there is no excess free copper, which would cause toxicity. A virtual orchestra of proteins are required to achieve copper homeostasis. For copper uptake, Cu(II) is first reduced to Cu(I) via a membrane-bound reductase. The reduced copper can then be internalised by a copper transporter where it is transferred to copper chaperones for transport and specific delivery to various organelles. Of significance are internal copper transporters, ATP7A and ATP7B, notable for their role in disorders of copper deficiency and toxicity, Menkes and Wilson’s disease, respectively. Metallothioneins and Cu/Zn superoxide dismutase can protect against excess copper in cells. It is clear too, increasing age, environmental and lifestyle factors impact on brain copper. Studies on AD suggest an important role for copper in the brain, with some AD therapies focusing on mobilising copper in AD brains. The transport of copper into the brain is complex and involves numerous players, including amyloid precursor protein, Aβ peptide and cholesterol.     

Influenza—an emerging and re-emerging disease

Influenza A viruses continue to emerge from the aquatic avian reservoir and cause pandemics. There are periodic exchanges of influenza virus genes or whole viruses between avians and other species giving rise to pandemics of diseases in humans, lower animals and birds. It is hypothesized that pigs are an intermediate host and that China is an epicenter for the evolution of human pandemic strains. However, the transmission of avian influenza viruses to pigs in Europe in 1979 and detection of reassortants with human influenza genes in pigs raises the question of whether the next pandemic of influenza will emerge in Europe!     

Serum zinc levels and Alzheimer’s disease

Concentrations of zinc in postmortem serum and four brain regions were measured by flame atomic absorption spectrometry and instrumental neutron activation analysis, respectively, in nine Alzheimer’s disease (AD) and eight control subjects. A statistically significant elevation of zinc serum was observed in AD subjects (136.4±66.8 μg/dL) compared with age-matched control subjects (71.1±35.0 μg/dL). No significant differences were observed between AD and control zinc concentrations in the amygdala, hippocampus, cerebellum, and superior and middle temporal gryi.     

Parkinson’s disease and enhanced inflammatory response

Parkinson’s disease (PD) is the first and second most prevalent motor and neurodegenerative disease, respectively. The clinical symptoms of PD result from a loss of midbrain dopaminergic (DA) neurons. However, the molecular cause of DA neuron loss remains elusive. Mounting evidence implicates enhanced inflammatory response in the development and progression of PD pathology. This review examines current research connecting PD and inflammatory response.     

Matrix-dependent perturbation of TGFβ signaling and disease

Transforming growth factor beta (TGFβ) is a multipotent cytokine that is sequestered in the extracellular matrix (ECM) through interactions with a number of ECM proteins. The ECM serves to concentrate latent TGFβ at sites of intended function, to influence the bioavailability and/or function of TGFβ activators, and perhaps to regulate the intrinsic performance of cell surface effectors of TGFβ signal propagation. The downstream consequences of TGFβ signaling cascades in turn provide feedback modulation of the ECM. This review covers recent examples of how genetic mutations in constituents of the ECM or TGFβ signaling cascade result in altered ECM homeostasis, cellular performance and ultimately disease, with an emphasis on emerging therapeutic strategies that seek to capitalize on this refined mechanistic understanding.