Tetrahydrobiopterin Availability in Parkinson’s and Alzheimer’s Disease; Potential Pathogenic Mechanisms

Within the central nervous system, tetrahydrobiopterin (BH4) is an essential cofactor for dopamine and serotonin synthesis. In addition, BH4 is now established to be an essential cofactor for all isoforms of nitric oxide synthase (NOS). Inborn errors of metabolism affecting BH4 availability are well documented and the clinical presentation can be attributed to a paucity of dopamine, serotonin, and nitric oxide (NO) generation. In this article, we have focussed upon the sensitivity of BH4 to oxidative catabolism and the observation that when BH4 is limiting some cellular sources of NOS may generate superoxide whilst other BH4 saturated NOS enzymes may be generating NO. Such a scenario could favor peroxynitrite generation. If peroxynitrite is not scavenged, e.g., by antioxidants such as reduced glutathione, irreversible damage to critical cellular enzymes could ensue. Such targets include components of the mitochondrial electron transport chain, alpha ketoglutarate dehydrogenase and possibly pyruvate dehydrogenase. Such a cascade of events is hypothesized, in this article, to occur in neurodegerative conditions such as Parkinson’s and Alzheimer’s disease.     

Vitellogenin’s putative role in <Emphasis Type="Italic">Tegillarca granosa</Emphasis>’s cadmium detoxification

The bloody clam, Tegillarca granosa, is a commercial benthic bivalve, having a strong accumulation ability and torrelence to cadmium. To investigate whether vitellogenin (Vg) is involved in cadmium (Cd) detoxification, the full-length cDNA of T. granosa Vg was cloned, and its expression pattern in response to cadmium exposure was studied compared with the reference metallothionein (MT) gene. The full T. granosa Vg sequence consisted of 8988 bp, including a 6930-bp open reading frame that encoded a 2309 amino acid polypeptide. The deduced Vg protein contained a Vg N-terminal domain, domain of unknown function (DUF1943), SbcC domain, and von Willebrand factor type D domain (VWD). Multiple metal-binding sites were predicted in the deduced T. granosa Vg protein, suggesting its potential in functioning as a metal-binding protein. In addition, Vg expression increased in the T. granosa digestive gland and hemolymph in time-dependent manner after exposure to 1, 3, 6 and 9 μg/L Cd for 28 days. MT expression was measured in parallel with Vg expression, and the latter was more sensitive to Cd induction than the former. Together, results of the present research suggested that Vg may play an important role in T. granosa metal detoxification.     

Chasing genes in Alzheimer’s and Parkinson’s disease

Alzheimers disease (AD), the most common type of dementia, and Parkinsons disease (PD), the most common movement disorder, are both neurodegenerative adult-onset diseases characterized by the progressive loss of specific neuronal populations and the accumulation of intraneuronal inclusions. The search for genetic and environmental factors that determine the fate of neurons during the ageing process has been a widespread approach in the battle against neurodegenerative disorders. Genetic studies of AD and PD initially focused on the search for genes involved in the aetiological mechanisms of monogenic forms of these diseases. They later expanded to study hundreds of patients, affected relative-pairs and population-based studies, sometimes performed on special isolated populations. A growing number of genes (and pathogenic mutations) is being identified that cause or increase susceptibility to AD and PD. This review discusses the way in which strategies of gene hunting have evolved during the last few years and the significance of finding genes such as the presenilins, -synuclein, parkin and DJ-1. In addition, we discuss possible links between these two neurodegenerative disorders. The clinical, pathological and genetic presentation of AD and PD suggests the involvement of a few overlapping interrelated pathways. Their imbricate features point to a spectrum of neurodegeneration (tauopathies, synucleinopathies, amyloidopathies) that need further intense investigation to find the missing links.     

Huntingtin’s Function in Axonal Transport Is Conserved in Drosophila melanogaster

Huntington’s disease (HD) is a devastating dominantly inherited neurodegenerative disorder caused by an abnormal polyglutamine expansion in the N-terminal part of the huntingtin (HTT) protein. HTT is a large scaffold protein that interacts with more than a hundred proteins and is probably involved in several cellular functions. The mutation is dominant, and is thought to confer new and toxic functions to the protein. However, there is emerging evidence that the mutation also alters HTT’s normal functions. Therefore, HD models need to recapitulate this duality if they are to be relevant. Drosophila melanogaster is a useful in vivo model, widely used to study HD through the overexpression of full-length or N-terminal fragments of mutant human HTT. However, it is unclear whether Drosophila huntingtin (DmHTT) shares functions similar to the mammalian HTT. Here, we used various complementary approaches to analyze the function of DmHTT in fast axonal transport. We show that DmHTT interacts with the molecular motor dynein, associates with vesicles and co-sediments with microtubules. DmHTT co-localizes with Brain-derived neurotrophic factor (BDNF)-containing vesicles in rat cortical neurons and partially replaces mammalian HTT in a fast axonal transport assay. DmHTT-KO flies show a reduced fast axonal transport of synaptotagmin vesicles in motoneurons in vivo. These results suggest that the function of HTT in axonal transport is conserved between flies and mammals. Our study therefore validates Drosophila melanogaster as a model to study HTT function, and its dysfunction associated with HD.     

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.     

Molecular pharming’s foot in the FDA’s door: Protalix’s trailblazing story

Objectives

This short commentary examines the factors that led to Food and Drug Administration’s approval of the first plant-derived biologic.

Results

In 2012, the first plant-derived protein pharmaceutical (biologic) was approved for commercial use in humans. The product, a recombinant form of human β-glucocerebrosidase marketed as ELELYSO, was developed by Protalix Biotherapeutics (Carmiel, Israel). The foresight to select this particular therapeutic product for development, flawless production pipeline, and serendipity seem to provide the key in explaining how ELELYSO became the first plant-derived biologic to achieve approval by Food and Drug Administration.

Conclusions

While the circumstances that enabled Protalix and its scientists to become the first to arrive at this historic milestone are perhaps unique, it is anticipated that more biologics will follow suit in winning regulatory endorsement.

     

Upset in response to a Sibling’s partner’s infidelities

Using data collected from people with at least one brother and one sister, and consistent with an evolutionary perspective, we find that older men and women (a) are more upset by a brother’s partner’s sexual infidelity than by her emotional infidelity and (b) are more upset by a sister’s partner’s emotional infidelity than by his sexual infidelity. There were no effects of participant sex or sex of in-law on upset over a sibling’s partner’s infidelities, but there was an effect of participant sex on reports of upset over one’s own partner’s infidelities. The results suggest that the key variable among older participants is the sex of the sibling or, correspondingly, the sex of the sibling’s partner, as predicted from an evolutionary analysis of reproductive costs, and not the sex of the participant, as predicted from a socialization perspective. Discussion offers directions for future work on jealousy.     

Alpha-interferon in Kikuchi’s disease

In Japan, histiocytic necrotizing lymphadenitis (Kikuchi’s disease) is a relatively common reactive lesion affecting lymph nodes, but the histogenesis and pathogenesis of the disease have not been clarified. Alpha-interferon has a role in the body’s defense against, viral infections. Using a polyclonal antibody to human alpha-interferon, we found numerous cells, mainly histiocytes, containing alpha-interferon in affected foci in the lymph nodes from 24 patients with Kikuchi’s disease. Tubuloreticular structures, thought by some authors to be associated with the production of interferon, were detected by electron microscopy in histiocytes, activated lymphocytes and vascular endothelial cells in the affected foci. These results suggested that the formation of tubuloreticular structures is a secondary phenomenon following stimulation by alpha-interferon. Further, the activity of 2′–5′ oligoadenylate synthetase, which is induced by alpha-interferon and enhanced during the early or active stage of viral infection, showed increased levels of activity in the active stage of Kikuchi’s disease and decreased to normal levels in the convalescent stage 2 weeks later. These results suggested the possibility of a viral etiology for Kikuchi’s disease.     

Catecholamine metabolism in children with Asperger’s and Kanner’s syndromes

In a stable state children with Asperger’s and Kanner’s syndromes demonstrate a similar decrease in plasma norepinephrine. In the aggravated state, these changes become more expressed and are characterized by a decrease in plasma tyrosine, norepinephrine, normetanephrine, and by an increase in dopamine and homovanillic acid and a decrease in excretion of norepinephrine and an increase in excretion of homovanillic acid, epinephrine and 3-methoxy-4-hydroxyphenylglycol (MHPG). In the aggravated state children with Kanner’s syndrome were characterized by increased plasma MHPG, decreased excretion of tyrosine and increased expression of normetanephrine. The observed imbalance in dopamine and epinephrine/norepinephrine systems suggests importance of combined analysis of changes in catecholamines and their metabolites as the most informative approach in the study of the effect of autistic disorders.     

What Explains Differences in Men’s and Women’s Production?

Researchers commonly use long-term average production inequalities to characterize cross-cultural patterns in foraging divisions of labor, but little is known about how the strategies of individuals shape such inequalities. Here, we explore the factors that lead to daily variation in how much men produce relative to women among Martu, contemporary foragers of the Western Desert of Australia. We analyze variation in foraging decisions on temporary foraging camps and find that the percentage of total camp production provided by each gender varies primarily as a function of men’s average bout successes with large, mobile prey. When men target large prey, either their success leads to a large proportional contribution to the daily harvest, or their failure results in no contribution. When both men and women target small reliable prey, production inequalities by gender are minimized. These results suggest that production inequalities among Martu emerge from stochastic variation in men’s foraging success on large prey measured against the backdrop of women’s consistent production of small, low-variance resources.

Maltotriose transport and utilization in Baker’s and Brewer’s yeast

Maltotriose is metabolized by baker’s and brewer’s yeast only oxidatively, with a respiratory quotient of 1.0, the being, depending on the strain used, 0–11, as compared with of 6–42μL CO₂ per h per mg dry substance. The transport appeared to proceed by facilitated diffusion (no effects of NaF, iodoacetamide and 3-chlorophenylhydrazonomalononitrile) with a K_T of more than 50mm and was inhibited by maltose > maltotriose > methyl-α-D-glucoside > maltotetraose >D-fruetose >D-glucose. The transport was present constitutively in bothSaccharomyces cerevisiae (baker’s yeast) and inS. uvarum (brewer’s yeast) and it was not significantly stimulated by preincubation with glucose or maltose. The pH optimum was 4.5–5.5, the temperature dependence yielded an activation energy of 26 kJ/mol.     

Mitochondrial Sirtuins in Parkinson’s Disease

Neurochemical Research - Parkinson’s disease (PD), the main risk factor for which is age, is one of the most common neurodegenerative diseases and imposes a substantial burden on affected...     

What’s in a loop?

DNAs and proteins are major classes of biomolecules that differ in many aspects. However, a considerable number of their members also share a common architectural feature that enables the assembly of multi-protein complexes and thereby permits the effective processing of signals: loop structures of substantial sizes. Here we briefly review a few representative examples and suggest a functional classification of different types of loop structures. In proteins, these loops occur in protein regions classified as intrinsically disordered. Studying such loops, their binders and their interactions with other loops should reveal much about cellular information computation and signaling network architectures. It is also expected to provide critical information for synthetic biologists and bioengineers.     

Thyroid hypofunction in Down’s syndrome

Oxidative stress affecting the thyroxin biosynthesis might explain the proneness of patients with Down's syndrome (DS) (trisomia 21) to develop hypothyroidism. Thyroideal cells are exposed to endogenous H2O2 that acts as a cofactor for the iodination of thyroxin precursors. The gland has high levels of selenium-containing proteins, including peroxide-detoxicating enzyme proteins. The object of the present study was to explore the hypothesis of a role of an imbalance between toxic oxygen production and protective metalloenzymes during the development of thyroid hypofunction in DS patients. We analyzed serum levels of thyroid hormones and trace metals in 38 institutionalized adults with DS, using mentally retarded subjects matched for age, sex, and behavioral function as controls. The DS patients had significantly lower mean values of free thyroxin (fT4) and increased TSH (thyroid stimulating hormone), as compared to the controls. They had lower serum selenium than the controls. A positive correlation was observed between serum concentrations of fT4 and selenium in the DS patients (r = 0.393, p < 0.05). No significant differences were found between the fT4 or the TSH concentrations in the patients with and without circulating antithyroid autoantibodies. Our results support the suggestion that thyroid hypofunction in patients with Down's syndrome in some way is linked to the low serum levels of selenium found in these patients. It is suggested that selenium-containing proteins are involved in thyroid hormonal synthesis, by protecting biosynthetic processes against the toxicity of free oxygen radicals.     

Women’s strategies in polygynous marriage

Both behavioral ecological and social anthropological analyses of polygynous marriage tend to emphasize the importance of competition among men in acquisition of mates, whereas the strategic options to women both prior to and after the establishment of a marriage have been neglected. Focusing on African marriage systems that are in some senses analogous to resource-defense polygyny, I first review the evidence of reproductive costs of polygyny to women. Then I discuss why the conflict of interests between men and women over mate number is often likely to be settled in favor of men. Using East African ethnographic data I examine the strategic responses of women and their families to polygynous marriage, focusing on four topics: mate choice (Kipsigis), attitudes toward incoming wives (Kipsigis), labor allocation and cooperation (comparative data, Kipsigis), and use of parental wealth (Datoga). The results of these quantitative analyses suggest that through a combination of judicious marriage choice and strategic responses within marriage, polygyny need not be costly to women in resource-defense polygynous systems. The conclusion is that a hierarchy of questions need to be addressed in the analysis of any polygynous marriage system.