Proteins in the nervous system — structure and function : Progress in clinical and biological research; volume 79

We have purified a unique enzyme, α-amino-?-caprolactam racemase 945-fold from an extract of Achromobacter obae by Octyl—Sepharose CL-4B and Thiopropyl—Sepharose 6B and some other chromatographies. The purified enzyme was found homogeneous by sodium dodecyl sulfate—polyacrylamide gel electrophoresis and analytical ultracentrifugation. The enzyme has a monomeric structure with M_r ～ 50 000 and a sedimentation coefficient (s_20,w) of 4.28 S. The enzyme contains pyridoxal 5'-phosphate as a coenzyme. The pH optimum for the enzyme activity is ～9.0. D- and L-α-amino-?-caprolactams are the only substrates. The K_m values for the D- and L-isomers are, 8 and 6 mM, respectively.     

Wnt signaling in the nervous system and in Alzheimer＇s disease

Wnts comprise a large family of proteins that have shown to be part of a signaling cascade that regulates several aspects of develop- ment including organogenesis, mid brain development as welt as stem cell proliferation. Wnt signaling pathway plays different roles in the development of neuronal circuits and also in the adult brain, where it regulates synaptic transmission and plasticity. It has been also implicated in various diseases including cancer and neurodegenerative diseases, reflecting its relevance in fundamental biological pro- cesses. This review summarizes the progress about Wnts function in mature nervous system with a focus on Alzheimer＇s disease （AD）. We discuss the prospects of modulating canonical and non-canonical Wnt signaling as a strategy for neuroprotection. This will include the potential of Wnts to： （i） act as potent regulators of hippocampai synapses and impact in learning and memory; （ii） regulate adult neurogenesis; and finally （iii） control AD pathogenesis.     

Prevalence of CD56 /NCAM molecule in nervous system immune system and endocrine glands--accidental coincidence?

The authors presented advances in the research on isoform of neural cell adhesion molecule CD56/NCAM, which appears to raise interest not only in biology, but also in clinical medicine. Molecular aspects of its synthesis have been presented and universal features of this protein have been underlined. It appears to play an important role in body homeostasis and especially in the interactions between neural, immune and endocrine systems. In relation to the immune system there are data suggesting significance of local protective and regulatory mechanisms in the liver linked to so called NKT (CD56+) cells. Main sites of prevalence of CD56/NCAM have been indicated both in physiology and pathology, especially in malignancy. CD56/NCAM incidence is common in tumors of neuroectodermal and endocrine origin. Besides it may be expressed on cells of several hemopoetic neoplasms originated both, from lymphoid and myeloid lineage. Moreover, the attention was paid to CD56/ NCAM expression in atypical sites as for example on epithelia of bile ducts in children with extrahepatic biliary atresia and on cells of pancreatic ducts in the course of chronic pancreatitis.     

Roles of transforming growth factor-α and related molecules in the nervous system

The epidermal growth factor (EGF) family of polypeptides is regulators for tissue development and repair, and is characterized by the fact that their mature forms are proteolytically derived from their integral membrane precursors. This article reviews roles of the prominent members of the EGF family (EGF, transforming growth factor-alpha [TGF-α] and heparin-binding EGF [HB-EGF]) and the related neuregulin family in the nerve system. These polypeptides, produced by neurons and glial cells, play an important role in the development of the nervous system, stimulating proliferation, migration, and differentiation of neuronal, glial, and Schwann precursor cells. These peptides are also neurotrophic, enhancing survival and inhibiting apoptosis of post-mitotic neurons, probably acting directly through receptors on neurons, or indirectly via stimulating glial proliferation and glial synthesis of other molecules such as neurotrophic factors. TGF-α, EGF, and neuregulins are involved in mediating glial-neuronal and axonal-glial interactions, regulating nerve injury responses, and participating in injury-associated astrocytic gliosis, brain tumors, and other disorders of the nerve system. Although the collective roles of the EGF family (as well as those of the neuregulins) are shown to be essential for the nervous system, redundancy may exist among members of the EGF family.     

Origin of the chordate central nervous system – and the origin of chordates

 Contrary to traditional views, molecular evidence indicates that the protostomian ventral nerve cord plus apical brain is homologous with the vertebrates’ dorsal spinal cord plus brain. The origin of the protostomian central nervous system from a larval apical organ plus longitudinal areas along the fused blastopore lips has been documented in many species. The origin of the chordate central nervous system is more enigmatic. About a century ago, Garstang proposed that the ciliary band of a dipleurula-type larva resembling an echinoderm larva should have moved dorsally and fused to form the neural tube of the ancestral chordate. This idea is in contrast to a number of morphological observations, and it is here proposed that the neural tube evolved through lateral fusion of a ventral, postoral loop of the ciliary band in a dipleurula larva; the stomodaeum should move from the ventral side via the anterior end to the dorsal side, which faces the substratum in cephalo- chordates and vertebrates. This is in accordance with the embryological observations and with the molecular data on the dorsoventral orientation. The molecular observations further indicate that the anterior part of the insect brain is homologous with the anterior parts of the vertebrate brain. This leads to the hypothesis that the two organs evolved from the same area in the latest common bilaterian ancestor, just anterior to the blastopore, with the protostome brain developing from the anterior rim of the blastopore (i.e. in front of the protostome mouth) and the chordate brain from an area in front of the blastopore, but behind the mouth (i.e. behind the deuterostome mouth). Received: 28 August 1998 / Accepted: 14 November 1998     

Can the insect nervous system synthesize ecdysteroids?

The term "neurosteroid" refers to both classic and unique steroid molecules that are synthesized from cholesterol (C) by the central and peripheral nervous systems of higher vertebrates. Therein, they accumulate and modulate nervous activity by a variety of mechanisms other than the classic steroid receptor-mediated modulation of genomic activity, although such may also be involved. Since the insect nervous system expresses ecdysteroid receptors and responds both directly and developmentally to ecdysteroids, the possibility of ecdysteroidogenesis in the pupal and adult central and peripheral nervous system of Manduca sexta and the nervous system of Drosophila melanogaster larvae was investigated. The endogenous concentrations of the critical, dietary-derived delta 5,7-sterols ergosterol and 7-dehydrocholesterol (7dC) remained 10 to 20-fold higher in the Manduca pupal and adult nervous tissues than was found in the larval hemolymph at the cessation of feeding. In addition, it was determined that the Manduca pupal nervous system, but not that of the adult, could synthesize 3H/14C-7dC or 3H-7-dehydro-25-hydroxycholesterol (3H-7d25C) from 3H/14C-cholesterol (3H/14C-C) or the polar sterol substrate 3H-25-hydroxycholesterol (3H-25C), respectively. However, none of the nervous system samples from the two species and the several stages analyzed, a small window of neural development in these insects, were capable of incorporating any of the above tracer precursor sterols into a radiolabelled ecdysteroid, i.e. less than 0.0005%. Thus, the absence of neurosteroidogenesis by the insect nervous system stands in sharp contrast to previously described nervous system steroid hormone biosynthesis by the mammalian nervous system.     

Angiotensin IV in the central nervous system

The mammalian brain harbors a renin-angiotensin system (RAS), which is independent from the peripheral RAS. Angiotensin II is a well-studied member of the RAS and exerts most of the known angiotensin-mediated effects on fluid and electrolyte homeostasis, autonomic activity, neuroendocrine regulation, and behavior. This review summarizes a mass of compelling new evidence for the biological role of an active (3-8) fragment of angiotensin II, named angiotensin IV. Angiotensin IV binds to a widely distributed binding site in the brain, but which is different from the known angiotensin II receptors AT1 and AT2. Angiotensin IV has been implicated in a number of physiological actions, including the regulation of blood flow, the modulation of exploratory behavior, and processes attributed to learning and memory. Furthermore, angiotensin IV may also be involved in neuronal development. Collectively, the available evidence suggests that angiotensin IV is a potent neuropeptide, involved in a broad range of brain functions.     

Did the ctenophore nervous system evolve independently?

Recent evidence supports the placement of ctenophores as the most distant relative to all other animals. This revised animal tree means that either the ancestor of all animals possessed neurons (and that sponges and placozoans apparently lost them) or that ctenophores developed them independently. Differentiating between these possibilities is important not only from a historical perspective, but also for the interpretation of a wide range of neurobiological results. In this short perspective paper, I review the evidence in support of each scenario and show that the relationship between the nervous system of ctenophores and other animals is an unsolved, yet tractable problem.     

N-cadherin and β1-integrins cooperate during the development of the enteric nervous system

Cell adhesion controls various embryonic morphogenetic processes, including the development of the enteric nervous system (ENS). Ablation of β1-integrin (β1-/-) expression in enteric neural crest cells (ENCC) in mice leads to major alterations in the ENS structure caused by reduced migration and increased aggregation properties of ENCC during gut colonization, which gives rise to a Hirschsprung's disease-like phenotype. In the present study, we examined the role of N-cadherin in ENS development and the interplay with β1 integrins during this process. The Ht-PA-Cre mouse model was used to target gene disruption of N-cadherin and β1 integrin in migratory NCC and to produce single- and double-conditional mutants for these two types of adhesion receptors. Double mutation of N-cadherin and β1 integrin led to embryonic lethality with severe defects in ENS development. N-cadherin-null (Ncad-/-) ENCC exhibited a delayed colonization in the developing gut at E12.5, although this was to a lesser extent than in β1-/- mutants. This delay of Ncad-/- ENCC migration was recovered at later stages of development. The double Ncad-/-; β1-/- mutant ENCC failed to colonize the distal part of the gut and there was more severe aganglionosis in the proximal hindgut than in the single mutants for N-cadherin or β1-integrin. This was due to an altered speed of locomotion and directionality in the gut wall. The abnormal aggregation defect of ENCC and the disorganized ganglia network in the β1-/- mutant was not observed in the double mutant. This indicates that N-cadherin enhances the effect of the β1-integrin mutation and demonstrates cooperation between these two adhesion receptors during ENS ontogenesis. In conclusion, our data reveal that N-cadherin is not essential for ENS development but it does modulate the modes of ENCC migration and acts in concert with β1-integrin to control the proper development of the ENS.     

γ-aminobutyric acid in the central nervous system of metamorphosing and mature Manduca sexta

We have begun to examine the factors controlling the accumulation of the neurotransmitter γ-aminobutyric acid (GABA) in the central nervous system (CNS) of the sphinx moth Manduca sexta. Analysis of soluble amino acids in CNS structures from mature moths outlines the regional distribution of GABA. Analysis of amino acids in the antennal lobes (the primary olfactory centres) of Manduca during metamorphosis reveals that GABA accumulates gradually and continuously through most of adult development until eclosion; within 18 hr after eclosion, levels of GABA abruptly increase 27–50%. The activity of the biosynthetic enzyme glutamic acid decarboxylase (EC 4.1.1.15), assayed in extracts of antennal lobes from developing moths, does not change after eclosion. Extracts of hemolymph from mature moths contain low levels of glutamate ( <0.2 mM) and higher levels of certain other amino acids such as serine, glutamine and proline. The concentration of proline in hemolymph increases up to 2-fold after eclosion. Glutamate, glutamine and proline are interconvertible in the CNS, and each can serve as precursor for GABA synthesis both in vivo and in vitro. The efficiency of the precursor role in vitro is similar for each amino acid, as estimated from the ratio of the specific radioactivities of GABA and glutamic acid in the ganglion derived from each precursor. Exogenous proline and glutamine can equilibrate rapidly with the ganglionic pools of the same amino acids while glutamic acid is relatively excluded. Taken together, the findings of this study show that proline and glutamine may contribute substantially to synthesis of GABA in the CNS of M. sexta.     

A single origin of the central nervous system?

As Denes et al. (2007) reveal in this issue, the expression profile and roles of genes that pattern the nervous system in embryos of chordates and annelids are surprisingly similar. This extraordinary conservation suggests that the patterning mechanism has been inherited largely unchanged from the bilaterian common ancestor and that the central nervous system, although dorsal in fish and ventral in worms, is an ancient characteristic of animals.     

μ Opiate receptor immunoreactivity in rat central nervous system

Immunoreactivity corresponding to the C-terminus of the rat μ opiate receptor can be detected by light microscopy in fiber- and terminal-like patterns in a number of rat brain and spinal cord regions, and in immunoreactive perikarya in several of these regions. Especially abundant fiber- and terminal-like patterns were localized to superficial layers of the spinal cord dorsal horn and nucleus caudalis of the spinal tract of the trigeminal, the nucleus of the solitary tract, nucleus ambiguous, locus coeruleus, interpeduncular nucleus, medial aspect of the lateral habenular nucleus, presumed “striasomes” of the caudate-putamen and nucleus accumbens. Moderate fiber and terminal densities were found in the ventral tegmental area, more medial aspects of the thalamus and hypothalamus, and several amygdaloid nuclei. Immunostained perikarya were prominent in the nucleus accumbens and also observed in the middle layers of the cerebral cortex, septum and diagonal band, preoptic area, medial thalamic and habenular nuclei, locus coeruleus, nucleus ambiguous, nucleus of the solitary tract, trigeminal nucleus caudalis and spinal cord substantia gelatinosa zones. Many of these localizations correspond well with the previously-determined autoradiographic distributions of μ opiate receptor ligand binding, and with reports of μ opiate receptor immunoreactivity determined using other antisera. Electron microscopic immunohistochemical studies reveal details of the membrane distribution of the μ receptor in nucleus accumbens, caudate/putamen, locus coeruleus, and spinal cord. These results suggest largely neuronal and largely extrasynaptic distributions of μ receptors that show differential patterns of perikaryal, dendritic, and/or axonal immunostaining in different central nervous system zones. Identification of these distributions adds substantially to data identifying the cellular localization of the principal opiate receptor involved in both analgesic and addictive processes. Special issue dedicated to Dr. Eric J. Simon.     

Are there differences between proseriates and lower flatworms in ultrastructure of the nervous system?

The ultrastructure of the CNS (central nervous system) in three species of the Proseriata — Archiloa unipunctata (O. Fabricius), Bothriomolus balticus (Meixner), and Promonotus schultzei (Meixner) — was studied and compared to that of the lower flatworms Stenostomum leucops (Catenulida) and Microstomum lineare (Macrostomida) in material available from our previous studies. Conventional electron microscopical fixation was used for A. unipunctata and B. balticus; the tannic-acid-incubation method (TARI), a method that reveals especially nonsynaptic exocytotic release of neuronal substances, was applied in study of P. schultzei.In general, the ultrastructural features of neurons and nerve fibers were similar in proseriates and lower flatworms. A striking feature common to both groups was the secretory appearance of all neurons. A significant difference between them is the occurrence, in the proseriates, of wrapping of neurons by glial cells. Heterogeneity in the population of neuronal vesicles and in structure of synapses in the proseriates are probably advanced characters; by contrast, S. leucops has relatively homogeneous vesicles and simple synapses. A gradual advancement from the state in the catenulids through that in the macrostomids to the proseriates seems to be reflected in the differentiation of synapses and the variability of neuronal vesicles. This probably reflects differences in functional demands but also evolutionary advancement.     

Genetic and epidemiologic analysis of hereditary diseases of the nervous system in the cities of Volgograd and Volzhskiĭ

A genetic epidemiological study of hereditary diseases of the nervous system (HDNS) was conducted in the cities of Volgograd and Volzhsky for the first time. In total, 1 323 500 individuals were examined including the populations of Volgograd and Volzhsky (1 012 800 and 310 700 persons, respectively). The prevalence of neurological diseases with autosomal dominant (AD), autosomal recessive (AR), and X-linked recessive inheritance was estimated. These data were compared with the estimates previously obtained for different population of the Russian Federation. A decrease was found in general HDNS load in Volgograd and Volzhsky. The compared populations were shown to differ in a contribution of AD, AR, and X-linked recessive diseases into the HDNS load formation. The possible effect of population dynamics factors on the HDNS load structure is discussed.     

Docosahexaenoic acid and cognitive function: Is the link mediated by the autonomic nervous system?

Docosahexaenoic acid is a long-chain polyunsaturated fatty acid that is found in large quantity in the brain and which has repeatedly been observed to be related in positive ways to both cognitive function and cardiovascular health. The mechanisms through which docosahexaenoic acid affects cognition are not well understood, but in this article, we propose a hypothesis that integrates the positive effects of docosahexaenoic acid in the cognitive and cardiovascular realms through the autonomic nervous system. The autonomic nervous system is known to regulate vital functions such as heart rate and respiration, and has also been linked to basic cognitive components related to arousal and attention. We review the literature from this perspective, and delineate the predictions generated by the hypothesis. In addition, we provide new data showing a link between docosahexaenoic acid and fetal heart rate that is consistent with the hypothesis.     

Protein kinase C isoforms in the enteric nervous system

C kinases (PKCs) are a family of enzymes essential for the transduction of signals in a diverse range of cell types, including neurons. The different isoforms vary in their activation requirements. Therefore, cell-specific expression of different isoforms has implications for PKC-mediated control of organ function. This study has investigated the types and distributions of PKC isoforms in the small intestine of the guinea-pig, with particular emphasis on their localisation in myenteric neurons, using immunohistochemistry and western blotting techniques. Three PKC isoforms, , and , were detected in the calbindin-immunoreactive subset of intrinsic primary afferent neurons, but not in other myenteric neurons. Both and immunoreactivities were also located in interstitial cells of Cajal. In contrast to these isoforms, immunoreactivity for PKCs and was present in all myenteric neurons of the ileum. PKC immunoreactivity was detected primarily in the glial network, as shown through double labelling with antibodies to the glial filament protein, S100b. Myenteric neurons were also weakly immunoreactive for this isoform. PKC immunoreactivity was very highly expressed in smooth muscle, but was largely absent from neurons. Immunoreactivity for RACK1, a binding protein for PKC, was detected in both calbindin-immunoreactive neurons and in smooth muscle cells. This study indicates a selective distribution of PKC isoforms to specific cell types. Isoform-specific activity of these enzymes could provide a means through which targeted modulation of intestinal function is achieved.     

Morphinome – proteome of the nervous system after morphine treatment

Summary. Proteome is a natural consequence of the post-genome era when the HUGO project (Human Genome Organization) has almost been completed. Here, a specifically aimed proteome in drug dependence – morphinome, is described, including tasks, strategies and pitfalls of the methodology.     

How does Mycobacterium leprae target the peripheral nervous system?

Mycobacterium leprae has the capacity to invade the peripheral nervous system and cause neuropathy. The molecular mechanisms responsible have remained unknown until recently. Identification of the endoneurial laminin-2 isoform and its receptor alpha-dystroglycan as neural targets of M. leprae has not only opened up a new area of scientific inquiry into the pathogenesis of neurological damage in leprosy, but has also revealed unexpected biological properties of these important host molecules.