Brain specificity

The cytokine leptin is secreted by adipocytes (fat cells) in proportion to the size of the adipose dq>ot and circulates via the bloodstream to the brain, where it ultimately affects feeding behavior, endocrine systems including reproductive function and, at least in rodents, energy expenditure. The major effect of Lqrtin is on the hy-pothalamous, where it suppresses appetite and hence food intake. Leptin exerts its effects via binding to the leptin receptor in the brain (specifically in the hypothalamus), which activates the JAK-STAT Pathway. 

Lawrence, L.J and Casida, J.E (1984). Interactions of lindane, toxaphene, and cyclodienes with brain-specific t-bntyl phosphorothionate receptor. Life Science 35, 171. 

Gleeson JG, Allen KM, Fox JW et al 1998 doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 92 63-72... 

Lund, E. G., Xie, C., Kotti, T., Turley, S. D., Dietschy, J. M. and Russell, D. W. Knockout of the cholesterol 24-hydroxy-lase gene in mice reveals a brain-specific mechanism of cholesterol turnover. /. Biol. Chem. 278 22980-22988, 2003. 

Lipids are transported between membranes. As indicated above, lipids are often biosynthesized in one intracellular membrane and must be transported to other intracellular compartments for membrane biogenesis. Because lipids are insoluble in water, special mechanisms must exist for the inter- and intracellular transport of membrane lipids. Vesicular trafficking, cytoplasmic transfer-exchange proteins and direct transfer across membrane contacts can transport lipids from one membrane to another. The best understood of such mechanisms is vesicular transport, wherein the lipid molecules are sorted into membrane vesicles that bud out from the donor membrane and travel to and then fuse with the recipient membrane. The well characterized transport of plasma cholesterol into cells via receptor-mediated endocytosis is a useful model of this type of lipid transport. [9, 20]. A brain specific transporter for cholesterol has been identified (see Chapter 5). It is believed that transport of cholesterol from the endoplasmic reticulum to other membranes and of glycolipids from the Golgi bodies to the plasma membrane is mediated by similar mechanisms. The transport of phosphoglycerides is less clearly understood. Recent evidence suggests that net phospholipid movement between subcellular membranes may occur via specialized zones of apposition, as characterized for transfer of PtdSer between mitochondria and the endoplasmic reticulum [21]. 

FIGURE B1-1 Glucose and monocarboxylic acid transporters in brain. Specific glucose and monocarboxylic acid transporters in brain are localized on different types of brain cells. (Courtesy of Ian Simpson and Susan Vannucci.)... 

Casida, J.E. and LJ. Lawrence. 1985. Structure-activity correlations for interactions of bicyclophosphorus esters and some polychlorocycloalkane and pyrethroid insecticides with the brain-specific t-butylcyclo-phosphorothionate receptor. Environ. Health Perspec. 61 123-132. 

Liu, Q. R., Lopdz-Corcuera, B., Mandiyan, S., Nelson, H and Nelson, N. (1993) Cloning and expression of a spinal cord- and brain-specific glycine transporter with novel structural... 

The recently identified brain-specific isoform of metallothionein, MT-III (neuronal growth inhibitory factor, GIF), has been linked with its potential role in neurophysiological and neuromodulatory functions (484). The human form of MT-III contains 68 amino acids with a 70% sequence (Fig. 23) similarity to other mammalian MTs and a... 

Fig. 23. The amino acid sequence of the brain-specific protein metallothionein III.

D. Sugiyama, H. Kusuhara, H. Taniguchi, S. Ishikawa, Y. Nozaki, H. Aburatani, and Y. Sugiyama. Functional characterization of rat brain-specific organic anion transporter (Oatpl4) at the blood-brain barrier High affinity transporter for thyroxine. J. Biol. Chem. 278 43489-43495 (2003). 

Chuang SS, Helvig C, Taimi M, Ramshaw HA, Collop AH, et al. 2004. CYP2U1, a novel human thymus- and brain-specific cytochrome P450, catalyzes omega- and (omega-1)-hydroxylation of fatty acids. J Biol Chem 279 6305-6314. 

The cytoskeleton is found near the axonal membrane and consists of microfilaments linked internally to microtubules and the plasma membrane by a network of filamentous protein that includes the brain-specific protein fodrin. This protein forms attachment sites for integral membrane proteins either by means of the neuronal cell adhesion molecule (N-CAM) or indirectly by means of a specific protein called ankyrin in the case of the sodium channels. This may provide a means whereby the sodium channels are concentrated in the region of the nodes of Ranvier. Thus the cortical cytoskeleton plays a vital role in neuronal function by acting as an attachment site for various receptors and ion channels, but also for s)maptic vesicles at nerve terminals, thereby providing a mechanism for concentrating the vesicles prior to the release of the neurotransmitter. 

With regard to transport capacity, the introduction of the anti-human insulin receptor antibody (HIR MAb) 83-14 as a vector indicates the potential for future improvements in brain-specific delivery vectors. Compared to anti-TfR monoclonal antibodies, the brain de-hvery in primates is over 7-fold higher due to the high PS product of the HIR MAb. 

Hitz C, Wurst W, Kuhn R (2007) Conditional brain-specific knockdown of MAPKusing Cre/ loxP regulated RNA interference. Nucleic Acids Res 35 e90... 

Makeyev EV, Zhang J, Carrasco MA et al (2007) The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol CeU 27 435-448... 

FIGURE 6.3 Construction of a brain-specific cDNA library. Messages (mRNA) are isolated from a tissue of interest. In this case, the target tissue is the brain. The mRNAs are converted to cDNA and each cDNA is inserted into the DNA of the bacteriophage lambda. The end result is a brain-specific cDNA library. 

FIGURE 6.4 Screening of a brain-specific cDNA library. Once a cDNA library is available, one can use it to isolate the sequence of any message that is in the library. One must have a portion of the gene to use as a probe. The library may need to be screened several times to isolate the full-length sequence of the gene of interest. 

J. N. Simpkins, J. McCormack, K. S. Estes, M. E. Brewster, E. Sheck, N. Bodor (1986). Sustained brain-specific delivery of estradiol causes long-term suppression of luteinizing hormone secretion. J. Med. Chem. 29 1809-1812. 

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