Apoptosis in Parkinson's disease: is p53 the missing link between genetic and sporadic Parkinsonism?

Parkinson's disease (PD) is a major age-related neurodegenerative disorder characterized by a massive and specific loss of dopaminergic neurons of the substantia nigra pars compacta. The cellular alterations are clinically translated into an invalidating movement disability associated to three canonical symptoms that are bradykinesia, resting tremor and rigidity. The exact causes of this neuronal loss are unknown, but a network of evidences indicates a major contribution of orchestrated cell death processes, also known as apoptosis. Apoptotic cell death is a normal process, the alteration of which triggers several pathologies including cancer and neurodegenerative disorders. Exhaustive work has been done to delineate the cellular mechanisms responsible for the exacerbated cell death of dopaminergic neurons observed in PD. Overall, the oncogene p53 has been identified as a key effector protein.This review will focus on the clues linking p53 to the etiology of PD and the evidences that this protein may be at the center of multiple signaling cascades not only altered by mutations of various proteins responsible for familial cases of PD but also on more general sporadic cases of this devastating disease.     

HLA-DR4 and career prospects in rheumatology: is there a link?

OBJECTIVE--To determine whether HLA type is associated with career progress in rheumatology. DESIGN--Comparison of HLA type after HLA analysis of samples of venous blood. SETTING--Department of Rheumatology Research, University of Birmingham. SUBJECTS--All (37) staff in the department. RESULTS--All the senior academics and most staff with a PhD expressed HLA-DR4. The prevalence of expression in each of these groups was significantly greater than that found in the controls. None of the junior doctors or secretaries expressed DR4. CONCLUSION--The junior doctors in the department have poor career prospects as HLA-DR4 seems to be associated with academic achievement.     

Epstein-Barr virus and rheumatoid arthritis: is there a link?

Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic, destructive, debilitating arthritis. Its etiology is unknown; it is presumed that environmental factors trigger development in the genetically predisposed. Epstein-Barr virus, a nearly ubiquitous virus in the human population, has generated great interest as a potential trigger. This virus stimulates polyclonal lymphocyte expansion and persists within B lymphocytes for the host's life, inhibited from reactivating by the immune response. In latent and replicating forms, it has immunomodulating actions that could play a role in the development of this autoimmune disease. The evidence linking Epstein-Barr virus and rheumatoid arthritis is reviewed.     

Climate change and amphibian declines: is there a link?

Abstract. Global climates have been changing, sometimes rapidly and dramatically, throughout the evolutionary history of amphibians. Therefore, existing amphibian species have been derived from those that have survived major climatic disturbances. Although recent global climate change has resulted in warming in many regions, temperatures in some areas to date have not changed measurably, or have even cooled. Declines of some amphibian populations have been correlated with climate events, but demonstrations of direct causal relationships need further research. Data are available indicating some indirect effect of climate change on the initiation of breeding activities of some amphibians that occur earlier than in previous springs, but the costs and benefits of these changes are just beginning to be investigated. Climate may also play an indirect role in facilitating epidemics of infectious disease. Regardless of the role that climate changes may have played in past and current amphibian declines, future shifts in climate, should they prove as dramatic as predicted, will certainly pose challenges for surviving amphibian populations and for successful recovery efforts of species that have suffered declines.     

Chemotactic signaling,microglia, and Alzheimer's disease senile plaques: is there a connection?

Chemotactic cells known as microglia are involved in the inflammation associated with pathology in Alzheimer’s disease (AD). We investigate conditions that lead to aggregation of microglia and formation of local accumulations of chemicals observed in AD senile plaques. We develop a model for chemotaxis in response to a combination of chemoattractant and chemorepellent signaling chemicals. Linear stability analysis and numerical simulations of the model predict that periodic patterns in cell and chemical distributions can evolve under local attraction, long-ranged repulsion, and other constraints on concentrations and diffusion coefficients of the chemotactic signals. Using biological parameters from the literature, we compare and discuss the applicability of this model to actual processes in AD. Reprint address. Maternity leave.     

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.     

Mutations in methylenetetrahydrofolate reductase and in cysthationine beta synthase: is there a link to homocysteine levels in peripheral arterial disease?

Peripheral arterial disease (PAD) is an atherosclerotic disturbance characterized by a progressive obstruction of lower limb arteries. Many risk factors associated with PAD development have being reported in the literature. The present study aimed to investigate whether mutations in the methylenetetrahydrofolate reductase (MTHFR) or in the cystathionine beta synthase (CBS) genes are associated with higher levels of homocysteine and the risk of PAD in patients from Brazil. This study analyzed 39 patients with PAD and 32 without PAD in whom risk factors and C677T mutations in the MTHFR gene and both 844ins68 and T833C mutations in the CBS gene were investigated. Although higher levels of homocysteine could be observed in patients with PAD compared to controls, no association between the increase of homocysteine and the frequency of C677T, 844ins68, and T833C mutations could be observed. The results suggest that these mutations do not appear to be related to either homocysteine levels or the development of the disease. However, hyperhomocysteinemia and smoking are important factors in PAD development.     

Neuropeptide Y, peptide YY and aluminum in Alzheimer's disease: is there an etiological relationship?

Neuropeptide Y (NPY) and peptide YY (PYY) are members of the pancreatic polypeptide family which have a high degree of primary and tertiary structural homology. They function as neurotransmitters and humoral agents in central nervous system and gastrointestinal function. During the last two decades, NPY body fluid concentrations and NPY/PYY brain receptor numbers have been demonstrated to be altered during the course of Alzheimer's disease. Recent research has shown that both NPY and PYY may be involved in aluminum metabolism in animal models. A brief discussion of the structure, biological activity and possible involvement of these peptides in aluminum metabolism and Alzheimer's disease is contained herein.     

Epstein–Barr virus and rheumatoid arthritis: is there a link?

Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic, destructive, debilitating arthritis. Its etiology is unknown; it is presumed that environmental factors trigger development in the genetically predisposed. Epstein–Barr virus, a nearly ubiquitous virus in the human population, has generated great interest as a potential trigger. This virus stimulates polyclonal lymphocyte expansion and persists within B lymphocytes for the host's life, inhibited from reactivating by the immune response. In latent and replicating forms, it has immunomodulating actions that could play a role in the development of this autoimmune disease. The evidence linking Epstein–Barr virus and rheumatoid arthritis is reviewed.     

Fbxw7α- and GSK3-mediated degradation of p100 is a pro-survival mechanism in multiple myeloma

Fbxw7α is a member of the F-box family of proteins, which function as the substrate-targeting subunits of SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complexes. Using differential purifications and mass spectrometry, we identified p100, an inhibitor of NF-κB signalling, as an interactor of Fbxw7α. p100 is constitutively targeted in the nucleus for proteasomal degradation by Fbxw7α, which recognizes a conserved motif phosphorylated by GSK3. Efficient activation of non-canonical NF-κB signalling is dependent on the elimination of nuclear p100 through either degradation by Fbxw7α or exclusion by a newly identified nuclear export signal in the carboxy terminus of p100. Expression of a stable p100 mutant, expression of a constitutively nuclear p100 mutant, Fbxw7α silencing or inhibition of GSK3 in multiple myeloma cells with constitutive non-canonical NF-κB activity results in apoptosis both in cell systems and xenotransplant models. Thus, in multiple myeloma, Fbxw7α and GSK3 function as pro-survival factors through the control of p100 degradation.     

Is Alzheimer's disease a systemic disease?

Although Alzheimer's disease (AD) is the most common neurodegenerative disease, the etiology of AD is not well understood. In some cases, genetic factors explain AD risk, but a high percentage of late-onset AD is unexplained. The fact that AD is associated with a number of physical and systemic manifestations suggests that AD is a multifactorial disease that affects both the CNS and periphery. Interestingly, a common feature of many systemic processes linked to AD is involvement in energy metabolism. The goals of this review are to 1) explore the evidence that peripheral processes contribute to AD risk, 2) explore ways that AD modulates whole-body changes, and 3) discuss the role of genetics, mitochondria, and vascular mechanisms as underlying factors that could mediate both central and peripheral manifestations of AD. Despite efforts to strictly define AD as a homogeneous CNS disease, there may be no single etiologic pathway leading to the syndrome of AD dementia. Rather, the neurodegenerative process may involve some degree of baseline genetic risk that is modified by external risk factors. Continued research into the diverse but related processes linked to AD risk is necessary for successful development of disease-modifying therapies.     

Is ammonia a pathogenetic factor in Alzheimer's disease?

An attempt was made to review experimental evidence in favor of the idea that ammonia plays a role in dementia of the Alzheimer type (DAT). Hyperammonemia causes biochemical and cellular dysfunctions in the brain, which can be found in brains of DAT patients. The most conspicuous among these findings are astrocytosis, impairment of glucose utilization, and a decreased rate of energy metabolism, and the impairment of neurotransmission, with a net increase in excitability and glutamate release. The derangement of lysosomal processing of proteins is another potential site of ammonia action. This aspect is especially important in view of the growing evidence for the role of the endosomal-lysosomal system in the formation of amyloidogenic fragments from -amyloid precursor protein. Ammonia is not considered a primary factor of the disease. However, since hyperammonemia and release of ammonia from the brains of DAT patients is well supported by published observations, ammonia should be taken into account as a factor that contributes to manifestations and the progression of DAT. If elevated ammonia concentrations turn out to be indeed as important in DAT, as is suggested in this review, rational therapeutic avenues can be envisaged that lead to the amelioration of symptoms and progression of the disease.Abbreviations -AP -amyloid protein - -APP -amyloid precursor protein - CNS central nervous system - DAT dementia of the Alzheimer type - GABA -aminobutyrate - MAO monoamine oxidase - NAD nicotinamide adenine dinucleotide This paper is dedicated to Rudi Vrba, a pioneer of the neurochemistry of ammonia, and a friend, at the occasion of his 68th birthday.     

Homocysteine and Alzheimer's disease: a modifiable risk?

A hypothesis is proposed that reconciles the epidemiological observation of elevated homocysteine in Alzheimer's disease (AD) with clinical features of the disease, particularly evidence of increased oxidative stress. We propose homocysteine is involved in an iron dysregulation/oxidative stress cycle that has a central role in the pathogenesis of AD. The implications of the hypothesis and some strategies for testing it are discussed.     

Climate change and outbreaks of amphibian chytridiomycosis in a montane area of Central Spain; is there a link?

Amphibian species are declining at an alarming rate on a global scale in large part owing to an infectious disease caused by the chytridiomycete fungus, Batrachochytrium dendrobatidis. This disease of amphibians has recently emerged within Europe, but knowledge of its effects on amphibian assemblages remains poor. Importantly, little is known about the environmental envelope that is associated with chytridiomycosis in Europe and the potential for climate change to drive future disease dynamics. Here, we use long-term observations on amphibian population dynamics in the Pe?alara Natural Park, Spain, to investigate the link between climate change and chytridiomycosis. Our analysis shows a significant association between change in local climatic variables and the occurrence of chytridiomycosis within this region. Specifically, we show that rising temperature is linked to the occurrence of chytrid-related disease, consistent with the chytrid-thermal-optimum hypothesis. We show that these local variables are driven by general circulation patterns, principally the North Atlantic Oscillation. Given that B. dendrobatidis is known to be broadly distributed across Europe, there is now an urgent need to assess the generality of our finding and determine whether climate-driven epidemics may be expected to impact on amphibian species across the wider region.     

Modeling Alzheimer's disease and other proteopathies in vivo: is seeding the key?

Summary.  Protein misfolding and aberrant polymerization are salient features of virtually all central neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease, triplet repeat disorders, tauopathies, and prion diseases. In many instances, a single amino acid change can predispose to disease by increasing the production and/or changing the biophysical properties of a specific protein. Possible pathogenic similarities among the cerebral proteopathies suggest that therapeutic agents interfering with the proteopathic cascade might be effective against a wide range of diseases. However, testing compounds preclinically will require disease-relevant animal models. Numerous transgenic mouse models of β-amyloidosis, tauopathy, and other aspects of AD have now been produced, but none of the existing models fully recapitulates the pathology of AD. In an attempt to more faithfully replicate the human disease, we infused dilute AD-brain extracts into Tg2576 mice at 3-months of age (i.e. 5–6 months prior to the usual onset of β-amyloid deposition). We found that intracerebral infusion of AD brain extracts results in: 1) Premature deposition of β-amyloid in eight month-old, β-amyloid precursor protein (βAPP)-transgenic mice (Kane et al., 2000); 2) augmented amyloid load in the injected hemisphere of 15 month-old transgenic mice; 3) evidence for the spread of pathology to other brain areas, possibly by neuronal transport mechanisms; and 4) tau hyperphosphorylation (but not neurofibrillary pathology) in axons passing through the injection site. The seeding of β-amyloid in vivo by AD brain extracts suggests pathogenic similarities between β-amyloidoses such as AD and other cerebral proteopathies such as the prionoses, and could provide a new model for studying the proteopathic cascade and its neuronal consequences in neurodegenerative diseases. Received June 28, 2001 Accepted August 6, 2001 Published online June 26, 2002