Role of proteolysis in polyglutamine disorders

To date, nine polyglutamine disorders have been characterised, including Huntington's disease (HD), spinobulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), and spinocerebellar ataxias 1, 2, 3, 6, 7 and 17 (SCAs). Although knockout and transgenic mouse experiments suggest that a toxic gain of function is central to neuronal death in these diseases (with the probable exception of SCA6), the exact mechanisms of neurotoxicity remain contentious. A further conundrum is the characteristic distribution of neuronal damage in each disease, despite ubiquitous expression of the abnormal proteins. One mechanism that could possibly underlie the specific distribution of neuronal toxicity is proteolytic cleavage of the full-length expanded polyglutamine tract-containing proteins. There is evidence found in vitro or in vivo (or both) of proteolytic cleavage in HD, SBMA, DRPLA, and SCAs 2, 3, and 7. In HD, cleavage has been demonstrated to be regionally specific, occurring as a result of caspase activation. These diseases are also characterised by development of intraneuronal aggregates of the abnormal protein that co-localise with components of the ubiquitin-proteasome pathway. It remains unclear whether these aggregates are pathogenic or merely disease markers; however, at least in the case of ataxin-3, cleavage promotes aggregation. Inhibition of specific proteases constitutes a potential therapeutic approach in these diseases.     

Near-total absence of the cerebellum.

We report five cases of near-total absence of the cerebellum with accompanying pontine hypoplasia. The cerebellar remnant in each case comprised only antero-superior masses, the posterior fossa being otherwise fluid filled. Three of these patients, two teenagers and an infant, presented a fairly consistent clinical and neuroradiological phenotype, and a few similar cases are recorded in the literature. The cerebellar remnant was irregular and asymmetrical, and no ventral pontine prominence was discernible. In at least the older two, cerebellar motor functions were not greatly compromised, and intellectual handicap was of a mild degree. We propose that these cases represent a distinct entity of "near-total absence of the cerebellum with flat ventral pons, and relatively mild clinical affection". All cases have been sporadic, implying that the risk of recurrence within a family may be low. Quite different clinical pictures, of considerably greater severity, are demonstrated in the remaining two cases. One had pontocerebellar hypoplasia type 2, while the other had a complex cerebellar and cerebral malformation.     

Molecular ontogeny of major neurotransmitter receptor systems in the mammalian central nervous system: norepinephrine, dopamine, serotonin, acetylcholine, and glycine

Neurotransmitter receptors are critical elements in intercellular signaling within the central nervous system and are divided into two major types based on their molecular structure and biophysical properties. The first are ionotropic receptors--ligand-gated ion channels that directly affect the membrane potential via passage of permeant ions (such as sodium and calcium) and mediate fast synaptic transmission. The second type are slower metabotropic receptors that are also ligand gated but depend on an interaction with guanine nucleotide-binding proteins and mediate signal transduction by activating second-messenger systems within the cell. In the past two decades, a wealth of information has emerged regarding the molecular biology and pharmacology of classic neurotransmitter receptors (including adrenergic, dopaminergic, serotonergic, cholinergic, glycine, gamma-aminobutyric acid [GABA(A)], and glutamate receptors). Further, the distribution of subunits comprising these receptors has been extensively studied. This review focuses on the molecular ontogeny of several of the major neurotransmitter receptor systems in the mammalian central nervous system, highlighting the role that some of these may play during brain development and in certain pathologic states.     

Living in the cold: freeze-induced gene responses in freeze-tolerant vertebrates

1. Winter survival for numerous cold-blooded animals includes freeze tolerance: the ability to endure the conversion of as much as 65% of total body water into extracellular ice. Selected molecular adaptations underlying freeze tolerance (e.g. cryoprotectants, ice nucleating proteins) have been widely studied, but the full range of metabolic adjustments needed for freeze endurance remains unknown. 2. Recent studies using gene screening techniques are providing a different approach to the search for biochemical responses that support freezing survival by identifying genes and proteins that are up-regulated by freezing or thawing in freeze-tolerant amphibians and reptiles. 3. Screening of a cDNA library from wood frog liver revealed the freeze-induced up-regulation of genes coding for the alpha- and gamma-subunits of fibrinogen (a plasma clotting protein), the mitochondrial ADP/ATP translocase and a novel 10 kDa protein containing a nuclear exporting sequence. 4. Northern blotting revealed that these genes were differentially responsive to two of the component stresses of freezing (dehydration and anoxia), indicating that different genes are induced by signals radiating either from cell volume change or oxygen deprivation during freezing. 5. Freeze up-regulation of fibrinogen synthesis in liver and other organs appears to be a damage repair response that anticipates a need for enhanced plasma clotting capacity to deal with ice crystal damage to capillary beds. 6. Up-regulation of ADP/ATP translocase in frog liver is linked with ischaemia resistance and studies with freeze-tolerant turtles have shown that other genes encoding proteins involved in mitochondrial energetics (NADH-ubiquinone oxido-reductase subunit 5, cytochrome C oxidase subunit 1) are also up-regulated by both anoxia and freezing exposures. 7. These studies are making major advances in our understanding of freeze tolerance as a natural phenomenon and also highlight new key areas that can be targeted by applied interventions for the optimization of medical cryopreservation techniques for cells, tissues and organs.     

Hydrogen ion and carbon dioxide content of the oviductal fluid of the rhesus monkey (Macaca mulatta).

The pH in the oviduct lumen of adult female rhesus monkey (Macaca mulatta) during the menstrual cycle was measured by means of miniaturized pH electrodes. Two types were used: one was a flexible electrode 1.4 mm in diameter; the other was a rigid electrode 0.8 mm in diameter. The same results were obtained with both types. For PCO2 measurements, the pH electrodes was converted to a Severinghaus tyep electrode covered with a Teflon membrane. During the follicular phase, the pH remains constant in the range 7.1 to 7.3. In association with ovulation, there is a sudden increase in the pH to the range 7.5 to 7.8. The pH remains high through the luteal phase. The PCO2 values obtained showed no evident changes with day of cycle. The range of values estimated was wide because of drift in electrode calibration, with the average level about 89 Torr, compared with 40 Torr for blood. At the average pH of 7.2 in the follicular phase, this value of PCO2 corresponds to 35 mM HCO3-; at the average pH of 7.6 of the secretory phase, this value corresponds to 90 mM HCO3-. This increase in pH and HCO3- after ovulation would be expected to enhance dispersal of corona cells during fertilization and to provide a favorable environment for the developing embryo.     

Income and race/ethnicity influence dietary fiber intake and vegetable consumption

Grains, fruits, and vegetables are the primary sources of dietary fiber (DF), with the white potato contributing nearly 7% of the DF to the US food supply. The DF composition of the white potato—with or without the skin and regardless of cooking method—compares well with the DF content of other vegetables. Many health benefits, including improved gastrointestinal health, are attributed to greater DF consumption; however, less than 3% of males and females have an adequate intake of DF. Because of this population-wide shortfall, DF is considered to be a nutrient of concern. In this study, using data from the National Health and Nutrition Examination Survey 2009 to 2010, we examined the mean intake of DF across sex, age, race/ethnicity, family income, and poverty threshold. This study shows that mean intake of DF is far below recommendations, with children and adolescents aged 2 to 19 years consuming an average of less than 14 g of DF per day. Adults 20+ years old consume, on average, about 17 g of DF per day, and men consume significantly more DF than women. Non-Hispanic black adults consume significantly less DF compared with other race/ethnic groups. Lower family income and living at less than 131% of poverty were associated with lower DF intakes among adults. Federal and local government policies should encourage consumption of all vegetables, including the white potato, as an important source of DF.