Adenosine A<Subscript>2A</Subscript> receptors in Parkinson’s disease treatment

Latest results on the action of adenosine A_2A receptor antagonists indicate their potential therapeutic usefulness in the treatment of Parkinson’s disease. Basal ganglia possess high levels of adenosine A_2A receptors, mainly on the external surfaces of neurons located at the indirect tracts between the striatum, globus pallidus, and substantia nigra. Experiments with animal models of Parkinson’s disease indicate that adenosine A_2A receptors are strongly involved in the regulation of the central nervous system. Co-localization of adenosine A_2A and dopaminergic D2 receptors in striatum creates a milieu for antagonistic interaction between adenosine and dopamine. The experimental data prove that the best improvement of mobility in patients with Parkinson’s disease could be achieved with simultaneous activation of dopaminergic D2 receptors and inhibition of adenosine A_2A receptors. In animal models of Parkinson’s disease, the use of selective antagonists of adenosine A_2A receptors, such as istradefylline, led to the reversibility of movement dysfunction. These compounds might improve mobility during both monotherapy and co-administration with L-DOPA and dopamine receptor agonists. The use of adenosine A_2A receptor antagonists in combination therapy enables the reduction of the L-DOPA doses, as well as a reduction of side effects. In combination therapy, the adenosine A_2A receptor antagonists might be used in both moderate and advanced stages of Parkinson’s disease. The long-lasting administration of adenosine A_2A receptor antagonists does not decrease the patient response and does not cause side effects typical of L-DOPA therapy. It was demonstrated in various animal models that inhibition of adenosine A_2A receptors not only decreases the movement disturbance, but also reveals a neuroprotective activity, which might impede or stop the progression of the disease. Recently, clinical trials were completed on the use of istradefylline (KW-6002), an inhibitor of adenosine A_2A receptors, as an anti-Parkinson drug.     

iPAD or PADi — ‘tablets’ with therapeutic disease potential?

The PAD enzymes.

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<Emphasis Type="Italic">Mycobacterium shimoidei</Emphasis>—cavitary pulmonary disease with favorable outcome

We report a case of cavitary pulmonary disease caused by Mycobacterium shimoidei in 67-year-old female with history of asthma. Even though susceptibility testing was not available, choice of treatment regimen (streptomycin, rifampicin, ethambutol, and clarithromycin), based on a few cases with favorable outcome reported in the literature, resulted with an excellent clinical, microbiological, and radiological response. This is the first report of pulmonary disease caused by M. shimoidei, but also the first ever isolation of M. shimoidei in Croatia.     

The redox chemistry of the Alzheimer's disease amyloid β peptide

There is a growing body of evidence to support a role for oxidative stress in Alzheimer's disease (AD), with increased levels of lipid peroxidation, DNA and protein oxidation products (HNE, 8-HO-guanidine and protein carbonyls respectively) in AD brains. The brain is a highly oxidative organ consuming 20% of the body's oxygen despite accounting for only 2% of the total body weight. With normal ageing the brain accumulates metals ions such iron (Fe), zinc (Zn) and copper (Cu). Consequently the brain is abundant in antioxidants to control and prevent the detrimental formation of reactive oxygen species (ROS) generated via Fenton chemistry involving redox active metal ion reduction and activation of molecular oxygen. In AD there is an over accumulation of the Amyloid β peptide (Aβ), this is the result of either an elevated generation from amyloid precursor protein (APP) or inefficient clearance of Aβ from the brain. Aβ can efficiently generate reactive oxygen species in the presence of the transition metals copper and iron in vitro. Under oxidative conditions Aβ will form stable dityrosine cross-linked dimers which are generated from free radical attack on the tyrosine residue at position 10. There are elevated levels of urea and SDS resistant stable linked Aβ oligomers as well as dityrosine cross-linked peptides and proteins in AD brain. Since soluble Aβ levels correlate best with the degree of degeneration [C.A. McLean, R.A. Cherny, F.W. Fraser, S.J. Fuller, M.J. Smith, K. Beyreuther, A.I. Bush, C.L. Masters, Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease, Ann. Neurol. 46 (1999) 860-866] we suggest that the toxic Aβ species corresponds to a soluble dityrosine cross-linked oligomer. Current therapeutic strategies using metal chelators such as clioquinol and desferrioxamine have had some success in altering the progression of AD symptoms. Similarly, natural antioxidants curcumin and ginkgo extract have modest but positive effects in slowing AD development. Therefore, drugs that target the oxidative pathways in AD could have genuine therapeutic efficacy.     

Genetic causes of Parkinson’s disease: <Emphasis Type="Italic">UCHL-1</Emphasis>

The ubiquitin proteasome system is an important cellular pathway that ubiquitinates damaged proteins and degrades them via the 26S proteasome. Abnormalities of this pathway can result in molecular protein aggregation and have been associated with Parkinsons disease (PD). UCHL-1, an enzyme central to the system, possesses catalytic hydrolase activity that can hydrolyze peptide-ubiquitin bonds and recycle ubiquitin monomers for re-use in the same process. Recently, UCHL-1 has been shown to possess a second dimerisation-dependent ligase activity and, at least in vitro, this ligase activity promotes alpha synuclein aggregation. UCHL-1 was first implicated in PD by the discovery of an I93M mutation identified in a German sib-pair with probable autosomal dominant PD. Although no further UCHL-1 mutations have been identified, a common non-synonymous S18Y polymorphism has been suggested to reduce disease susceptibility in non-mendelian forms of PD. In vitro functional data support this protective effect, with evidence that S18Y possesses reduced ligase activity compared with wild type UCHL-1. One study has found increased hydrolase activity associated with S18Y, although another study has not. Important issues regarding UCHL-1 and its role in PD remain inconclusive, especially regarding the pathogenicity of the mendelian I93M mutation. This review tries to address some of these uncertainties.D.G.H. is a clinical research fellow at the Institute of Neurology, Queen Square and is supported by a grant from the UK Parkinsons Disease Society (grant no. 4073). P.A.S. is supported by a grant from the Brain Research Trust (grant no. 6AAC). N.W.W. is supported by the UK Parkinsons Disease Society (grant no. 4029)     

Hypertrophic cardiomyopathy family with double-heterozygous mutations; does disease severity suggest doubleheterozygosity?

Background. With the improvement in genetic testing over time, double-heterozygous mutations are more often found by coincidence in families with hypertrophic cardiomyopathy (HCM). Double heterozygosity can be a cause of the wellknown clinical diversity within HCM families. Methods and results. We describe a family in which members carry either a single mutation or are double heterozygous for mutations in myosin heavy chain gene (MYH7) and cysteine and glycine-rich protein 3 (CSRP3). The described family emphasises the idea of a more severe clinical phenotype with double-heterozygous mutations. It also highlights the importance of cardiological screening where NT-proBNP may serve as an added diagnostic tool. Conclusion. With a more severe inexplicable phenotype of HCM within a family, one should consider the possibility of double-heterozygous mutations. This implies that in such families, even when one disease-causing mutation is found, all the family members still have an implication for cardiological screening parallel to extended genetic screening. (Neth Heart J 2009;17:458–63.)     

Shell disease in crustaceans – just chitin recycling gone wrong?

The exoskeletons of aquatic crustaceans and other arthropods contain chitin, a biopolymer of β-(1,4)-linked N -acetylglucosamine together with associated proteins. Despite the vast amounts of chitin within such animals little is found in sediments and open water because microorganisms rapidly degrade this following its loss after moulting or upon the animals' death. Shell disease syndrome is a worldwide disease condition that affects a wide range of crustaceans. It comes about as a result of bacterial degradation of the exoskeleton leading to unsightly lesions and even death if the underlying tissues become infected. There are at least two potential forms of the disease; one that appears to centre around chitin degradation and an additional form termed 'epizootic' shell disease, in which chitin degradation is of less significance. This account reviews our current understanding of the causative agents of this syndrome, assesses the potential economic consequences of the disease, and critically examines whether it is associated with anthropogenic disturbances including pollution. Overall, despite extensive studies during the last few decades, the potential links between faecal, heavy metal and insecticide pollution and shell disease are still unclear.     

Causes of Parkinson’s disease: genetics of <Emphasis Type="Italic">DJ-1</Emphasis>

The identification of Mendelian mutations in rare forms of familial Parkinsons disease (PD) have provided significant insights into the molecular pathogenesis of this common complex disorder. DJ-1 is the third of four genes known to be definitively causal in familial PD, the three others being -synuclein, parkin and the recently identified PINK1. Mutations in the DJ-1 gene were identified in two European families, a Dutch kindred harbouring a large homozygous genomic deletion encompassing exons 1–5 of the gene and an Italian kindred with a homozygous L166P missense mutation. The clinical phenotype of the two families was similar to that of parkin cases. Age of onset was in the mid-thirties with good responsiveness to l-dopa and slow disease progression. Focal dystonias and blepharospasm were also evident as were behavioural disturbances early in the course of the disease. To date, there are no studies of pathological material from known DJ-1 patients. It therefore remains to be determined whether these patients form Lewy bodies and/or Lewy neurites, the eosinophilic fibrillary inclusions that contain predominantly -synuclein and that are the pathological hallmark of PD.     

Could co‐transplantation of iPS cells derived hepatocytes and MSCs cure end‐stage liver disease?

Orthotopic liver transplantation is, to date, the only proven effective treatment for end-stage liver disease. However, it suffers from lack of donors and immunorejection. Here, we speculate that co-transplantation of induced pluripotent stem (iPS) cells derived hepatocytes and mesenchymal stem cells (MSCs) may offer an alternative way to treat patients with end-stage liver disease. Recently, progress on iPS cells, homogeneous differentiation of hepatocyte-like cells from embryonic stem cells (ESCs), and paracrine effects by MSCs highlight the possibility. Safe, efficient and rapid generation of iPS cells has been reliably produced by several experimental laboratories. Methods for highly efficient and homogeneous differentiation of ESCs into functional hepatocytes have been established as well. Moreover, paracrine effects by MSCs have been proven to play an important role in liver regeneration and repair, and the effects can be used as an enhancer for engraftment. All of these remarkable developments lead to this hypothesis which may offer a novel therapeutic strategy for treatment of patients with end-stage liver disease, though some issues about safety and efficacy need to be further guaranteed.     

The role of caspases in Alzheimer’s disease; potential novel therapeutic opportunities

Although apoptosis plays a critical role in molding the CNS into its final appearance and function, inappropriate activation of this pathway in the aging brain may contribute to neurodegeneration. In Alzheimer’s disease (AD), an overwhelming body of evidence supports the activation of apoptosis in general, and caspases specifically as an early event that may not only contribute to neurodegeneration but also promote the underlying pathology associated with this disease. Therefore, caspase inhibitors may provide an effective strategy for treating AD. However, despite the compelling evidence indicating a role for caspases in disease progression, chronic treatment with caspase inhibitors in animal models of AD has never been undertaken. In this review the role of caspases in AD will be addressed, including recent studies utilizing in vivo transgenic mouse models of tauopathies. In addition, a discussion of the therapeutic value and dangers of targeting caspase inhibition in the treatment of AD using caspase inhibitors such as Q-VD-OPh will be evaluated.     

Spontaneous conformational change within the prion protein—implications for disease pathogenesis?

A recent paper by Leclerc et al(1) describes how recombinant hamster prion protein can undergo a spontaneous change in conformation to a structure that has features in common with PrP(Sc). Structural change in the host prion protein, PrP(C) to an insoluble and aggregated form with increased beta-sheet content (PrP(Sc)) is central to the pathology of prion diseases.(2) A detailed understanding of the nature of these conformational changes will increase our knowledge of the molecular basis of prion pathology. These findings may have implications for how the disease is initiated and provide a format for further investigation.     

Atg7 in development and disease: panacea or Pandora’s Box?

Macroautophagy is an evolutionarily conserved intracellular degradation system used by life ranging from yeasts to mammals. The core autophagic machinery is composed of ATG (autophagy-related) protein constituents. One particular member of the ATG protein family, Atg7, has been the focus of recent research. Atg7 acts as an E1-like activating enzyme facilitating both microtubule-associated protein light chain 3 (LC3)-phosphatidylethanolamine and ATG12 conjugation. Thus, Atg7 stands at the hub of these two ubiquitin-like systems involving LC3 and Atg12 in autophagic vesicle expansion. In this review, I focus on the pleiotropic function of Atg7 in development, maintenance of health, and alternations of such control in disease.     

Polymorphisms of extrinsic death receptor apoptotic genes (FAS −670 G&gt;A,FASL −844 T&gt;C) in coronary artery disease

Apoptosis plays an important role in atherogenesis and rupture of vulnerable plaques in coronary artery disease. FAS and FAS ligand (FASL) induce apoptosis when FAS binds to FAS-L. However sFas blocks apoptosis by binding to FAS and FASL or sFasL. The present study is sought to examine the role of extrinsic apoptotic genes (FAS, FASL) polymorphism and serum levels of FAS, FASL in the pathogenesis and susceptibility to CAD in south Indian population. The study included 300 CAD patients and 300 healthy controls. Lipid profiles, sFas, sFasL were estimated by commercially available kits. FAS ?670 G>A, FASL ?844 T>C genotypes were analyzed by PCR–RFLP. Secondary structures of pre mRNA were analyzed by the Vienna RNA webserver and gene–gene and gene–environment interactions were determined by MDR analysis. Total cholesterol, triglyceride and LDL levels were significantly high in CAD patients compared to the controls. Molecular analysis revealed that the frequency of the AA genotype of FAS (54 % vs 27 %) and CC genotypes of FASL (10.3 % vs 1.3 %) were high in CAD patients compared to controls. Secondary structure analysis of FAS and FASL confirmed our molecular analysis. sFas levels were low while serum sFasL were high in CAD patients. MDR analysis revealed synergistic effects of gene polymorphisms and additive effects of epidemiological factors on risk of CAD. Polymorphisms of FAS (?670 G/A), FASL (?844 T/C) and their circulating levels play an important role in the pathology of CAD.     

A meta–QTL analysis of disease resistance traits of <Emphasis Type="Italic">Theobroma cacao</Emphasis> L.

Theobroma cacao, is a tropical understorey tree that is a major economic resource to several tropical countries. However, the crop is under increased threat from several diseases that are responsible for 30% loss of harvest globally. Although QTL data related to the genetic determinism of disease resistance exist in cocoa, QTL mapping experiments are heterogeneous, thus making comparative QTL mapping essential for marker assisted selection (MAS). Sixteen QTL experiments were analysed, and the 76 QTLs detected were projected on a progressively established consensus map. Several hot spots, with QTLs related to different Phytophthora species and other diseases, were observed. The likely number of “real” QTLs was estimated by using a meta-analysis implemented in BioMercator software. There was a twofold reduction in average confidence interval observed when compared to the confidence interval of individual QTLs. This alternative approach confirms the existence of several sources of resistance to different diseases of cocoa which could be cumulated in new varieties to increase the sustainability of cocoa resistance using MAS strategies.     

Ca<Superscript>2+</Superscript>-induced permeability transition in human lymphoblastoid cell mitochondria from normal and Huntington’s disease individuals

Huntingtons disease (HD) is associated with expansion of polyglutamine tract in a protein named huntingtin (htt) that is expressed in virtually all body tissues. Thus mutated htt (HD-htt) might affect all organs, although clinical manifestations of HD are associated with selective loss of corticostriatal neurons of the brain. In this work we studied how HD-htt affects mitochondria in human peripheral blood cells. We compared various functions of mitochondria isolated from cultured lymphoblastoid cells derived from three HD patients with juvenile onset of the disease (HD-LBM) and three age-matched control (C-LBM) individuals. Respiratory parameters in different metabolic states, with succinate and glutamate plus malate were the same for all control and HD cell lines. State 4 membrane potential in HD-LBM was slightly lower than in C-LBM. The calcium retention capacity (CRC) of mitochondria was estimated using simultaneously several methods to register permeability transition (PT). We found that LBM do not undergo swelling upon Ca²⁺-induced PT, and do not increase CRC in the presence of ADP + oligomycin. Although each cell line had different CRC values, qualitatively PT was different in C-LBM and HD-LBM. With C-LBM cyclosporin A (CsA) increased CRC significantly, while with HD-LBM CsA was ineffective. In C-LBM depolarization of mitochondria and a large pore opening (PT) always occurred simultaneously. In HD-LBM depolarization occurred at 20–50% lower Ca²⁺ loads than PT. We suggest that HD-htt promotes low H⁺ conductance of the mitochondria by interacting with proteins at the contacts sites without directly promoting PT or hampering mitochondrial oxidative phosphorylation. (Mol Cell Biochem 269: 143–152, 2005)     

<Emphasis Type="Italic">Caenorhabditis elegans</Emphasis> as an experimental tool for the study of complex neurological diseases: Parkinson’s disease,Alzheimer’s disease and autism spectrum disorder

The nematode Caenorhabditis elegans has a very well-defined and genetically tractable nervous system which offers an effective model to explore basic mechanistic pathways that might be underpin complex human neurological diseases. Here, the role C. elegans is playing in understanding two neurodegenerative conditions, Parkinson’s and Alzheimer’s disease (AD), and a complex neurological condition, autism, is used as an exemplar of the utility of this model system. C. elegans is an imperfect model of Parkinson’s disease because it lacks orthologues of the human disease-related genes PARK1 and LRRK2 which are linked to the autosomal dominant form of this disease. Despite this fact, the nematode is a good model because it allows transgenic expression of these human genes and the study of the impact on dopaminergic neurons in several genetic backgrounds and environmental conditions. For AD, C. elegans has orthologues of the amyloid precursor protein and both human presenilins, PS1 and PS2. In addition, many of the neurotoxic properties linked with Aβ amyloid and tau peptides can be studied in the nematode. Autism spectrum disorder is a complex neurodevelopmental disorder characterised by impairments in human social interaction, difficulties in communication, and restrictive and repetitive behaviours. Establishing C. elegans as a model for this complex behavioural disorder is difficult; however, abnormalities in neuronal synaptic communication are implicated in the aetiology of the disorder. Numerous studies have associated autism with mutations in several genes involved in excitatory and inhibitory synapses in the mammalian brain, including neuroligin, neurexin and shank, for which there are C. elegans orthologues. Thus, several molecular pathways and behavioural phenotypes in C. elegans have been related to autism. In general, the nematode offers a series of advantages that combined with knowledge from other animal models and human research, provides a powerful complementary experimental approach for understanding the molecular mechanisms and underlying aetiology of complex neurological diseases.     

Does the p75 neurotrophin receptor mediate Aβ‐induced toxicity in Alzheimer's disease?

Alzheimer's disease is characterized by the over-production and accumulation of amyloidogenic Abeta peptide, which can induce cell death in vitro. It has been suggested that the death signal could be transduced by the pan neurotrophin receptor (p75NTR). p75NTR is well known for its ability to mediate neuronal death in neurodegenerative conditions and is inextricably linked with changes that occur in Alzheimer's disease. Moreover, Abeta binds to p75NTR, activating signalling cascades. However, the complexity of p75NTR-mediated signalling, which does not always promote cell death, leaves open the possibly of Abeta promoting death via an alternative signalling pathway or the regulation of other p75NTR-mediated actions. This review focuses on the interactions between Abeta and p75NTR in the context of the broader p75NTR signalling field, and offers alternative explanations for how p75NTR might contribute to the aetiology of Alzheimer's disease.