The Human Central Nervous System

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  2. Stem and progenitor cell–based therapy of the human central nervous system | Nature Biotechnology
  3. Atlas of Human Central Nervous System Development
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Morphologically, central nervous system CNS neurons differ in size, number and complexity of dendrites, number of synaptic connections, length of axons and distance across which synaptic connections are established, extent of axonal myelination, and other cellular characteristics. Neuronal diversity is also amplified by the inclusion of chemical specificity on the basis of the neurotransmitters, which they use for chemical transmission or neuromodulation. This great diversity among neuronal populations is a strong indication that although all neurons contain the same genetic code in their genome, each neuronal population has their own gene expression profile.

While the diversity of neuronal structures and functions are well documented, what is less appreciated is the diverse response of neurons to stresses and adverse factors during aging or as a result of neurodegenerative diseases. In this scenario of cellular diversity emerges the concept of selective neuronal vulnerability SNV. SNV is described as the differential sensitivity of neuronal populations in the nervous system to stresses that cause cell damage or death and can lead to neurodegeneration [ 1 , 2 ].

The fact that specific regions of the nervous system exhibit differential vulnerabilities to aging and various neurodegenerative diseases is a reflection of both the specificity in the aetiology of each disease and of the heterogeneity in neuronal and non-neuronal responses to cell-damaging processes associated with each of the diseases [ 3 ]. The appearance of SNV is not limited to cross-regional differences in the nervous system, as within a single e. Among these cell-damaging processes one could count inflammatory, proteotoxicity, vascular and many other pathophysiological processes, including an excess of lipid peroxidation see later.

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Oxidative stress OS is involved in the basic mechanisms of nervous system aging; whilst an excessive oxidation has been invoked as an etiopathogenic or physiopathologic mechanism for neurodegeneration. Oxidative stress, the result of an imbalance between production of free radicals and the enzymatic or non-enzymatic detoxification of these highly reactive species, is detrimental to cells because free radicals chemically modify lipids, proteins, and nucleic acids.

So, it is very important to define the vulnerability of the different neuronal populations in terms of susceptibility to oxidative stress in physiological conditions in order to extent this knowledge to improve our understanding of how this particular form of cell vulnerability causes selective neuronal losses in nervous system, as well as reveal potential molecular and cellular mechanisms that bring about relative resistance or sensitivity of neurons to stresses. Chemical reactions in cells of the nervous system are under strict enzyme control and conform to a tightly regulated metabolic program in order to minimize unnecessary side reactions.

Nevertheless, apparently uncontrolled and potentially deleterious reactions occur, even under physiological conditions. Reactive oxygen species ROS express a variety of molecules and free radicals chemical species with one unpaired electron physiologically generated from the metabolism of molecular oxygen [ 4 ].

They are extremely reactive and have damaging effects. Superoxide anion, the product of a one-electron reduction of oxygen, is the precursor of most ROS and a mediator in oxidative chain reactions [ 4 ] Figure 1. The character of radical is not circumscribed to oxygen containing species, as nitrogen, chloride and sulphide containing molecules could also play a significant role. Globally, in cells of the CNS the major sites of physiological ROS generation are the complex I and III of the mitochondrial electron transport chain, which contains several redox centers flavins, iron—sulphur clusters, and ubisemiquinone capable of transferring one electron to oxygen to form superoxide anion [ 5 , 6 ].

Oxidative damage is a broad term used to cover the attack upon biological molecules by free radicals. The three main physiological ROS. MnSOD and Gpx are antioxidants enzymes. All living organisms have lipid membranes. Biological membranes are dynamic structures that generally consist of bilayers of amphipathic molecules hold together by non-covalent bonds [ 7 ].

Phospholipids, consisting of a hydrophilic head group with attached hydrophobic acyl chains, are the predominant membrane lipids and are, from a topographic point of view, asymmetrically distributed across the bilayer. The variation in head groups and aliphatic chains allows the existence of a huge range of different phospholipid species [ 8 , 9 ]. The acyl chains are either saturated, monounsaturated or polyunsaturated hydrocarbon chains that normally vary from 14 to 22 carbons in length Figure 2 , with an average chain length strictly maintained around 18 carbon atoms, and a relative distribution between saturated and unsaturated fatty acids of SFA and UFA, respectively [ 10 ].

Polyunsaturated fatty acids PUFAs are essential components of cellular membranes that strongly affect their fluidity, flexibility and selective permeability, as well as many cellular and physiological processes [ 11 ]. Long-chain polyunsaturated fatty acids are highly enriched in the nervous system.

Stem and progenitor cell–based therapy of the human central nervous system | Nature Biotechnology

Docosahexaenoic acid DHA; n-3; 4,7,10,13,16,C , in particular, is the most abundant PUFA in the brain and is concentrated in aminophospholipids of cell membranes. Numerous studies have indicated that this concentration of DHA in the nervous system is essential for optimal neuronal functions. Although the underlying mechanisms of its essential function are still not clearly understood, emerging evidence suggests that unique metabolism of DHA in relation to its incorporation into neuronal membrane phospholipids plays an important role.

Accretion of DHA in the CNS actively occurs during the developmental period, primarily relying on circulating plasma DHA derived from diet or from biosynthesis in the liver [ 12 ]. However, local biosynthesis of DHA also occurs in the brain, providing an alternative source of DHA for its accumulation in the brain [ 13 ].

DHA thus formed is transferred back to the ER and quickly incorporated into membrane phospholipids by esterification during de novo synthesis or by a deacylation-reacylation reaction. Long-chain n-6 fatty acids are biosynthesized from linoleic acid n-6; 9,C using the analogous pathway and the same enzyme system Figure 3.

In most tissues, the commonly observed long-chain n-6 fatty acid is arachidonic acid AA; n-6; 5,8,11,C The liver is considered to be the primary site for biosynthesis of DHA, which becomes available to brain uptake through subsequent secretion into the circulating blood stream. Among neural cells, consisting of neurons, astrocytes, microglia, and oligodendrocytes, the capacity to synthesize DHA has been demonstrated only in astrocytes [ 13 ].

Despite the fact that neurons are major targets for DHA accumulation, they cannot produce DHA because of lack of desaturase activity. Cerebromicrovascular endothelia can also elongate and desaturate shorter carbon chain fatty acids. However, they cannot perform the final desaturation step to produce either n-6 or n-3 [ 17 ].

Long chain and very long-chain fatty acid biosynthesis in mammals. The long chain saturated fatty acids and unsaturated fatty acids of the n, n-7 and n -9 series can be synthesized from palmitic acid C produced by the fatty acid synthase FAS. Long-chain fatty acids of the n-6 and n-3 series can only be synthesized from precursors obtained from dietary precursors DIET. Elovl, elongation of very long chain fatty acids fatty acid elongase ; Fads, fatty acid desaturases.

DHA synthesis in astrocytes is negatively influenced by the availability of preformed DHA [ 18 ] and thus may represent a quantitatively minor source for the neural DHA accretion when the circulating DHA supply is adequate. Incorporation of circulating DHA across the blood brain barrier appears to be an important route for maintaining adequate levels of DHA in the brain.

Generally, it is difficult to deplete DHA from the neural membranes of adult mammals even with a DHA low diet, presumably because of preferential uptake of DHA into the brain to support the basal turnover. In the case of insufficient supply of n-3 fatty acids during development, the loss of DHA does occur but is compensated with DPAn-6 through reciprocal replacement, suggesting a requirement of very long-chain, highly unsaturated fatty acids in neural membranes.

Whether brain DHA is derived from the circulating plasma pool or biosynthesized locally, in the astrocytes, which are situated in close contact with neurons, appear to play an important role in supplying DHA to neurons. DHA can be released readily from astroglial membranes under basal and stimulated conditions, and supplied to neurons. Despite its high abundance in neuronal membranes, DHA is not easily released but is tenaciously retained in the neuronal membranes under the conditions in which AA can be released. Considering the fact that astroglia support neurons by providing neurotrophic factors, DHA supplied by astroglia may also be trophic.

Indeed, DHA has been shown to promote neuronal survival [ 20 ] and differentiation [ 21 ] in both transformed and primary neuronal cells in culture. The susceptibility of membrane phospholipids to oxidative demise is related to two inherent traits, the physico-chemical properties of the membrane bilayer and the intrinsic chemical reactivity of the fatty acids composing the membrane [ 10 , 22 ].

The first property is related to the fact that oxygen and free radicals are more soluble in the fluid lipid bilayer than in the aqueous solution. Thus, membranes contain an interior organic phase in which the oxygen may tend to concentrate. The second property is related to the fact that PUFA residues of phospholipids are extremely sensitive to oxidation. Every membrane phospholipid contains an unsaturated fatty acid residue esterified to the 2-hydroxyl group of its glycerol moiety.

Atlas of Human Central Nervous System Development

Many of these are polyunsaturated and the presence of a methylene group between two double bonds renders the fatty acid more sensitive to ROS-induced damage. Therefore, the sensitivity of these molecules to oxidation increase exponentially as a function of the number of double bonds per fatty acid molecule [ 22 , 23 ]. Consequently, the high concentration of PUFAs in phospholipids not only makes them prime targets for reaction with oxidizing agents but also enables them to participate in long free radical chain reactions.

Reactive free radicals can pull off hydrogen atoms from PUFA side chains.

Human Central Nervous System

This hydrogen is bonded to a carbon in the fatty acid backbone by a covalent bond. The resulting peroxyl radical is highly reactive: it can attack membrane proteins and oxidize adjacent PUFA side chains. So, the reaction is repeated and the whole process continues in a free radical chain reaction, generating lipid hydroperoxides [ 4 ]. Lipid hydroperoxides are more hydrophilic than unperoxidized fatty acid side chains.

They try to migrate to the membrane surface to interact with water, thus disrupting the membrane structure, altering fluidity and other functional properties and making the membrane leaky. Additionally, a number of other short chain aldehydes are produced during lipid peroxidation through poorly understood mechanisms. These carbonyl compounds, ubiquitously generated in biological systems, have unique properties contrasted with free radicals.

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Thus, compared with reactive oxygen and nitrogen species, reactive aldehydes have a much longer half-life i. Further, the non-charged structure of aldehydes allows them to migrate relatively ease through hydrophobic membranes and hydrophilic cytosolic media, thereby extending the migration distance far from the production site.

Based on these features alone, these carbonyl compounds can be more destructive than ROS and may have far-reaching damaging effects on target sites within or outside membranes. For the same reason, their long half-life allows them to subserve as second-messenger, signalling for important cellular responses in a mostly unknown fashion. General structures of principal lipoxidative reactive carbonyl species detected in biological systems. Carbonyl compounds react with nucleophilic groups in macromolecules like proteins, DNA, and aminophospholipids, among other, resulting in their chemical, nonenzymatic, and irreversible modification and formation of a variety of adducts and crosslinks collectively named Advanced Lipoxidation Endproducts ALEs [ 10 , 25 , 26 ] Figure 5.

The accumulation of MDA adducts on proteins is also involved in the formation of lipofuscin a nondegradable intralysosomal fluorescent pigment formed through lipoxidative reactions. Lipid peroxidation-derived endproducts can also react at the exocyclic amino groups of deoxyguanosine, deoxyadenosine, and deoxycytosine to form various alkylated products.

Guanine is, however, the most commonly modified DNA base because of its high nucleophilicity. Thus, the most common adducts arising from enals are exocyclic adducts such as etheno adducts, and MDA-deoxyguanosine M1dG. Finally, the amino group of aminophospholipids can also react with carbonyl compounds and initiate some of the reactions ocurring in proteins and DNA, leading to the formation of adducts like MDA-phosphatidylethanolamine, and carboxymethyl-phosphatidylethanolamine [ 10 ].

Reactive carbonyl species react with nucleophilic groups in macromolecules A, proteins; B, DNA resulting in their chemical, nonenzymatic, and irreversible modification and formation of a variety of adducts and crosslinks collectively named Advanced Lipoxidation Endproducts ALEs.

DNA lipoxidative damage is present in the genome of healthy humans and other animal species at biologically significant levels similar or even higher that oxidation markers sensu stricto. DNA damage is mutagenic, carcinogenic, and have powerful effects on signal transduction pathways [ 28 ].


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Finally, the amino group of aminophospholipids can also react with carbonyl compounds and initiate some of the reactions occurring in proteins [ 29 ]. Biological processes involving aminophospholipids could be potentially affected by this process. Among these processes, it may be highlighted i asymmetrical distribution of aminophospholpids in cellular and different subcellular membranes; ii translocation between and lateral diffusion in the membrane; iii membrane physical properties; iv biosynthesis and turnover of membrane phospholipids; and v activity of membrane-bound proteins that require aminophospholipids for their function.

The peroxidation of the PUFA chains of phospholipids generates a complex mixture of carbonyl compounds. Thus, available studies support the notion that superoxide radical produced by the mitochondrial electron transport chain can cause mild uncoupling of mitochondria by activating the membrane proton conductance by uncoupling proteins UCPs. Insight into the molecular mechanism by which superoxide radical activates UCPs comes from the finding that the lipid peroxidation product 4-HNE and its homologs induce uncoupling of mitochondria through UCPs and also through the adenine nucleotide translocase [ 30 ].

This and other observations support a model in which endogenous superoxide production generates carbon-centred radicals that initiate lipid peroxidation, producing alkenals like 4-HNE that activate UCPs and adenine nucleotide translocase. So, UCPs respond to overproduction of matrix superoxide by catalyzing mild uncoupling, which lower proton motive force and would decrease superoxide production by the electron transport chain. This negative feedback loop will protect cells from ROS-induced damage and might represent the ancestral function of all UCPs. PMID: This entry form currently does not support special characters.