Neurodegenerative Diseases
Original Paper
RNA-Targeted Suppression of Stress-Induced Allostasis in Primate Spinal Cord NeuronsEvron T. · Moyal-Segal L.B. · Lamm N. · Geffen A. · Soreq H.Department of Biological Chemistry, Institute of Life Sciences, and the Israel Center of Neuronal Computation, The Hebrew University of Jerusalem, Jerusalem, Israel
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Neurodegenerative Dis 2005;2:16–27
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Article / Publication Details
First-Page Preview
Received: March 29, 2005
Accepted: April 21, 2005
Published online: August 10, 2005
Issue release date: August 2005
Number of Print Pages: 12
Number of Figures: 5
Number of Tables: 1
ISSN: 1660-2854 (Print)
eISSN: 1660-2862 (Online)
For additional information: https://www.karger.com/NDD
Abstract
Peripheral acetylcholine levels notably control the synthesis in macrophages of pro-inflammatory cytokines; however, it remains unclear whether this peripheral regulatory pathway affects central nervous system neurons. To explore the interrelationship between neuronal cholinergic homeostasis and peripheral inflammatory responses in primates, we used spinal cord sections from cynomolgus monkeys after 7 days oral or intravenous treatment with Monarsen oligonucleotide. Monarsen is an antisense oligonucleotide 3′-protected by 2′-oxymethylation, which was proved to induce selective destruction of the stress-induced acetylcholinesterase splice variant AChE-R mRNA. Handling stress predictably suppressed neuronal choline acetyl transferase (ChAT) and the vesicular acetylcholine transporter (VAChT) in all treated monkeys. In Monarsen-treated animals, we further observed suppression of stress-induced increases in plasma AChE activities. Corresponding decreases in AChE-R mRNA were seen in spinal cord neurons, associated with parallel decline patterns in the mRNA encoding for the splice factor SC35 (the levels of which co-increase with those of AChE-R) as well as in the neuronal pro-inflammatory interleukins IL-1β and IL-6. The antisense effects showed direct dose dependence and were inversely associated with neuronal cell size. These findings suggest a causal association between neuronal cholinergic allostasis and inflammatory reactions in primates and support the peripheral use of RNA-targeted intervention with AChE-R accumulation for the management of both stress and inflammatory responses.
© 2005 S. Karger AG, Basel
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References
- Borovikova LV, Ivanova S, Zhang M, et al: Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000;405:458–462.
- Tracey KJ, Warren HS: Human genetics: an inflammatory issue. Nature 2004;429:35–37.
- Tracey KJ: The inflammatory reflex. Nature 2002;420:853–859.
- Orr CF, Rowe DB, Halliday GM: An inflammatory review of Parkinson’s disease. Prog Neurobiol 2002;68:325–340.
- Weiner HL, Selkoe DJ: Inflammation and therapeutic vaccination in CNS diseases. Nature 2002;420:879–884.
-
Soreq H, Seidman S: Acetylcholinesterase – new roles for an old actor. Nat Rev Neurosci 2001;2:294–302.
External Resources
- Kaufer D, Friedman A, Seidman S, Soreq H: Acute stress facilitates long-lasting changes in cholinergic gene expression. Nature 1998;393:373–377.
- Weihe E, Tao-Cheng JH, Schafer MK, Erickson JD, Eiden LE: Visualization of the vesicular acetylcholine transporter in cholinergic nerve terminals and its targeting to a specific population of small synaptic vesicles. Proc Natl Acad Sci USA 1996;93:3547–3552.
- Brenner T, Hamra-Amitay Y, Evron T, Boneva N, Seidman S, Soreq H: The role of readthrough acetylcholinesterase in the pathophysiology of myasthenia gravis. FASEB J 2003;17:214–222.
- Grisaru D, Deutsch V, Shapira M, et al: ARP, a peptide derived from the stress-associated acetylcholinesterase variant, has hematopoietic growth promoting activities. Mol Med 2001;7:93–105.
- Birikh KR, Sklan EH, Shoham S, Soreq H: Interaction of ‘readthrough’ acetylcholinesterase with RACK1 and PKCbeta II correlates with intensified fear-induced conflict behavior. Proc Natl Acad Sci USA 2003;100:283–288.
- Tavitian B, Terrazzino S, Kuhnast B, et al: In vivo imaging of oligonucleotides with positron emission tomography. Nat Med 1998;4:467–471.
-
Kasuya E, Mizuno M, Watanabe G, Terasawa E: Effects of an antisense oligodeoxynucleotide for neuropeptide Y mRNA on in vivo luteinizing hormone-releasing hormone release in ovariectomized female rhesus monkeys. Regul Pept 1998;75–76:319–325.
- Prut Y, Fetz EE: Primate spinal interneurons show pre-movement instructed delay activity. Nature 1999;401:590–594.
- Becker CM, Schmieden V, Tarroni P, Strasser U, Betz H: Isoform-selective deficit of glycine receptors in the mouse mutant spastic. Neuron 1992;8:283–289.
- McGehee DS, Krasowski MD, Fung DL, Wilson B, Gronert GA, Moss J: Cholinesterase inhibition by potato glycoalkaloids slows mivacurium metabolism. Anesthesiology 2000;93:510–519.
- Subramony SH, Mitsumoto H, Mishra SK: Motor neuropathy associated with a facilitating myasthenic syndrome. Muscle Nerve 1986;9:64–68.
- Wang CX, Olschowka JA, Wrathall JR: Increase of interleukin-1beta mRNA and protein in the spinal cord following experimental traumatic injury in the rat. Brain Res 1997;759:190–196.
- Svensson I, Waara L, Johansson L, Bucht A, Cassel G: Soman-induced interleukin-1beta mRNA and protein in rat brain. Neurotoxicology 2001;22:355–362.
- Meshorer E, Biton IE, Inbal E, Ben-Shaul Y, Ben-Ari S, Assaf Y, Soreq H, Cohen Y: Chronic cholinergic imbalances promote brain diffusion and transport abnormalities. FASEB J 2005;19:910–922.
- Tacke R, Manley JL: Determinants of SR protein specificity. Curr Opin Cell Biol 1999;11:358–362.
- Wang HY, Xu X, Ding JH, Bermingham JR Jr, Fu XD: SC35 plays a role in T cell development and alternative splicing of CD45. Mol Cell 2001;7:331–342.
- Pick M, Flores-Flores C, Grisaru D, Shochat S, Deutsch V, Soreq H: Blood-cell-specific acetylcholinesterase splice variations under changing stimuli. Int J Dev Neurosci 2004;22:523–531.
- Perry C, Sklan EH, Birikh K, et al: Complex regulation of acetylcholinesterase gene expression in human brain tumors. Oncogene 2002;21:8428–8441.
- Cohen O, Erb C, Ginzberg D, et al: Neuronal overexpression of ‘readthrough’ acetylcholinesterase is associated with antisense-suppressible behavioral impairments. Mol Psychiatry 2002;7:874–885.
- Perry C, Sklan EH, Soreq H: CREB regulates AChE-R-induced proliferation of human glioblastoma cells. Neoplasia 2004;6:279–286.
- Sklan EH, Lowenthal A, Korner M, et al: Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in health, risk factors, exercise training, and genetics study. Proc Natl Acad Sci USA 2004;101:5512–5517.
- Benmoyal-Segal L, Vander T, Shifman S, et al: Acetylcholinesterase/paraoxonase interactions increase the risk of insecticide-induced Parkinson’s disease. FASEB J 2005;19:452–454.
- Bryk B, Benmoyal-Segal L, Podoly E, et al: Inherited and acquired interactions between ACHE and PON1 polymorphisms modulate plasma acetylcholinesterase and paraoxonase activities. J Neurochem 2005;92:1216–1227.
- Chan RY, Adatia FA, Krupa AM, Jasmin BJ: Increased expression of acetylcholinesterase T and R transcripts during hematopoietic differentiation is accompanied by parallel elevations in the levels of their respective molecular forms. J Biol Chem 1998;273:9727–9733.
- Erickson JD, Weihe E, Schafer MK, et al: The VAChT/ChAT ‘cholinergic gene locus’: new aspects of genetic and vesicular regulation of cholinergic function. Prog Brain Res 1996;109:69–82.
- Barber RP, Phelps PE, Houser CR, Crawford GD, Salvaterra PM, Vaughn JE: The morphology and distribution of neurons containing choline acetyltransferase in the adult rat spinal cord: an immunocytochemical study. J Comp Neurol 1984;229:329–346.
- Meshorer E, Erb C, Gazit R, et al: Alternative splicing and neuritic mRNA translocation under long-term neuronal hypersensitivity. Science 2002;295:508–512.
- Nijholt I, Farchi N, Kye M, et al: Stress-induced alternative splicing of acetylcholinesterase results in enhanced fear memory and long-term potentiation. Mol Psychiatry 2004;9:174–183.
- Galyam N, Grisaru D, Grifman M, et al: Complex host cell responses to antisense suppression of ACHE gene expression. Antisense Nucleic Acid Drug Dev 2001;11:51–57.
- Grisaru D, Lev-Lehman E, Shapira M, et al: Human osteogenesis involves differentiation-dependent increases in the morphogenically active 3′ alternative splicing variant of acetylcholinesterase. Mol Cell Biol 1999;19:788–795.
- Deutsch VR, Pick M, Perry C, et al: The stress-associated acetylcholinesterase variant AChE-R is expressed in human CD34(+) hematopoietic progenitors and its C-terminal peptide ARP promotes their proliferation. Exp Hematol 2002;30:1153–1161.
- Geary RS, Watanabe TA, Truong L, et al: Pharmacokinetic properties of 2′-O-(2-methoxyethyl)-modified oligonucleotide analogs in rats. J Pharmacol Exp Ther 2001;296:890–897.
- Opalinska JB, Gewirtz AM: Nucleic-acid therapeutics: basic principles and recent applications. Nat Rev Drug Discov 2002;1:503–514.
- Hacker G, Redecke V, Hacker H: Activation of the immune system by bacterial CpG-DNA. Immunology 2002;105:245–251.
- Hartmann G, Weeratna RD, Ballas ZK, et al: Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J Immunol 2000;164:1617–1624.
- Roberts TL, Sweet MJ, Hume DA, Stacey KJ: Cutting Edge: Species-specific TLR9-mediated recognition of CpG and non-CpG phosphorothioate-modified oligonucleotides. J Immunol 2005;174:605–608.
- Hellstrom-Lindahl E, Gorbounova O, Seiger A, Mousavi M, Nordberg A: Regional distribution of nicotinic receptors during prenatal development of human brain and spinal cord. Brain Res Dev Brain Res 1998;108:147–160.
- Wang H, Yu M, Ochani M, et al: Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003;421:384–388.
- Ban E, Haour F, Lenstra R: Brain interleukin-1 gene expression induced by peripheral lipopolysaccharide administration. Cytokine 1992;4:48–54.
- Quan N, Sundar SK, Weiss JM: Induction of interleukin-1 in various brain regions after peripheral and central injections of lipopolysaccharide. J Neuroimmunol 1994;49:125–134.
- Pitossi F, del Rey A, Kabiersch A, Besedovsky H: Induction of cytokine transcripts in the central nervous system and pituitary following peripheral administration of endotoxin to mice. J Neurosci Res 1997;48:287–298.
- Nguyen KT, Deak T, Owens SM, et al: Exposure to acute stress induces brain interleukin-1beta protein in the rat. J Neurosci 1998;18:2239–2246.
- Turrin NP, Gayle D, Ilyin SE, et al: Pro-inflammatory and anti-inflammatory cytokine mRNA induction in the periphery and brain following intraperitoneal administration of bacterial lipopolysaccharide. Brain Res Bull 2001;54:443–453.
- Ek M, Kurosawa M, Lundeberg T, Ericsson A: Activation of vagal afferents after intravenous injection of interleukin-1beta: role of endogenous prostaglandins. J Neurosci 1998;18:9471–9479.
- Melamed S, Shirom A, Toker S, Berliner S, Shapira I: Association of fear of terror with low-grade inflammation among apparently healthy employed adults. Psychosom Med 2004;66:484–491.
- Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C, Malarkey WB, Glaser R: Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc Natl Acad Sci USA 2003;100:9090–9095.
- Sureau A, Soret J, Guyon C, et al: Characterization of multiple alternative RNAs resulting from antisense transcription of the PR264/SC35 splicing factor gene. Nucleic Acids Res 1997;25:4513–4522.
-
Shaw PJ, Eggett CJ: Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis. J Neurol 2000;247(suppl 1):I17–I27.
External Resources
- Cifuentes-Diaz C, Frugier T, Tiziano FD, et al: Deletion of murine SMN exon 7 directed to skeletal muscle leads to severe muscular dystrophy. J Cell Biol 2001;152:1107–1114.
- Bjartmar C, Trapp BD: Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Curr Opin Neurol 2001;14:271–278.
- Sendtner M: Molecular mechanisms in spinal muscular atrophy: models and perspectives. Curr Opin Neurol 2001;14:629–634.
- Hund E: Neurological complications of sepsis: critical illness polyneuropathy and myopathy. J Neurol 2001;248:929–934.
- Shytle RD, Mori T, Townsend K, et al: Cholinergic modulation of microglial activation by alpha7 nicotinic receptors. J Neurochem 2004;89:337–343.
- Darreh-Shori T, Almkvist O, Guan ZZ, et al: Sustained cholinesterase inhibition in AD patients receiving rivastigmine for 12 months. Neurology 2002;59:563–572.
- Li Y, Liu L, Kang J, et al: Neuronal-glial interactions mediated by interleukin-1 enhance neuronal acetylcholinesterase activity and mRNA expression. J Neurosci 2000;20:149–155.
- Tomkins O, Kaufer D, Korn A, et al: Frequent blood-brain barrier disruption in the human cerebral cortex. Cell Mol Neurobiol 2001;21:675–691.
- Pollak Y, Gilboa A, Ben-Menachem O, Ben-Hur T, Soreq H, Yirmiya R: Acetylcholinesterase inhibitors reduce brain and blood interleukin-1β production. Ann Neurol 2005;57:741–745.
Article / Publication Details
First-Page Preview
Received: March 29, 2005
Accepted: April 21, 2005
Published online: August 10, 2005
Issue release date: August 2005
Number of Print Pages: 12
Number of Figures: 5
Number of Tables: 1
ISSN: 1660-2854 (Print)
eISSN: 1660-2862 (Online)
For additional information: https://www.karger.com/NDD
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