Complex Host Cell Responses to Antisense Suppression of<i>ACHE</i>Gene Expression

Galyam, N.; Grisaru, Dan; Grifman, Mirta; Melamed-Book, Naomi; Eckstein, Fritz; Seidman, Shlomo; Eldor, Amiram; Soreq, Hermona

doi:10.1089/108729001750072128

Cited by 21 publications

(13 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The selective destruction of AChE-R mRNA in this study is compatible with previous studies in mice [11,25,33,34] , rats [9] and human cells [26,[35][36][37] . The animal and human cell culture studies cited above used inverse oligonucleotides for controls, showing the sequence specifi city of Monarsen's effect.…”

Section: Discussionsupporting

confidence: 91%

RNA-Targeted Suppression of Stress-Induced Allostasis in Primate Spinal Cord Neurons

Evron

Moyal-Segal²,

Lamm³

et al. 2005

Neurodegener Dis

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 91%

RNA-Targeted Suppression of Stress-Induced Allostasis in Primate Spinal Cord Neurons

Evron

Moyal-Segal²,

Lamm³

et al. 2005

Neurodegener Dis

View full text Add to dashboard Cite

show abstract

“…AChE mRNA labeling at nuclear foci has been characterized as responsive to antisense treatment [16,48] , supporting the notion that AChE mRNA transcripts are subject to dynamic recycling in these sites.…”

Section: Pas Blockade Of Extracellular Ache Induces Intracellular Tramentioning

confidence: 59%

Peripheral Site Acetylcholinesterase Blockade Induces RACK1-Associated Neuronal Remodeling

Farchi

Ofek²,

Podoly³

et al. 2007

Neurodegener Dis

View full text Add to dashboard Cite

Background: Peripheral anionic site (PAS) blockade of acetylcholinesterase (AChE) notably affects neuronal activity and cyto-architecture, however, the mechanism(s) involved are incompletely understood. Objective: We wished to specify the PAS extracellular effects on specific AChE mRNA splice variants, delineate the consequent cellular remodeling events, and explore the inhibitory effects on interchanging RACK1 interactions. Methods: We exposed rat hippocampal cultured neurons to BW284C51, the peripheral anionic site inhibitor of AChE, and to the non-selective AChE active site inhibitor, physostigmine for studying the neuronal remodeling of AChE mRNA expression and trafficking. Results: BW284C51 induced overexpression of both AChE splice variants, yet promoted neuritic translocation of the normally rare AChE-R, and retraction of AChE-S mRNA in an antisense-suppressible manner. BW284C51 further caused modest decreases in the expression of the scaffold protein RACK1 (receptor for activated protein kinase βII), followed by drastic neurite retraction of both RACK1 and the AChE homologue neuroligin1, but not the tubulin-associated MAP2 protein. Accompanying BW284C51 effects involved decreases in the Fyn kinase and membrane insertion of the glutamate receptor NR2B variant and impaired glutamatergic activities of treated cells. Intriguingly, molecular modeling suggested that direct, non-catalytic competition with Fyn binding by the RACK1-interacting AChE-R variant may be involved. Conclusions: Our findings highlight complex neuronal AChE-R/RACK1 interactions and are compatible with the hypothesis that peripheral site AChE inhibitors induce RACK1-mediated neuronal remodeling, promoting suppressed glutamatergic neurotransmission.

show abstract

“…Indeed, attenuation of AChE expression by EN101 (Galyam et al, 2001), but not by the inverse oligonucleotide INV101 (12 g/ml), significantly limited the BW284c51-induced suppression of glutamate currents (Fig. 3E), indicating that AChE overexpression disrupts glutamatergic functions.…”

Section: Pas Blockade Impairs Glutamate Receptor Functionmentioning

confidence: 95%

Excessive Expression of Acetylcholinesterase Impairs Glutamatergic Synaptogenesis in Hippocampal Neurons

Dong¹,

Yun²,

Farchi³

et al. 2004

J. Neurosci.

View full text Add to dashboard Cite

Acetylcholinesterase (AChE) exerts noncatalytic activities on neural cell differentiation, adhesion, and neuritogenesis independently of its catalytic function. The noncatalytic functions of AChE have been attributed to its peripheral anionic site (PAS)-mediated proteinprotein interactions. Structurally, AChE is highly homologous to the extracellular domain of neuroligin, a postsynaptic transmembrane molecule that interacts with presynaptic ␤-neurexins, thus facilitating synaptic formation and maturation. Potential effects of AChE expression on synaptic transmission, however, remain unknown. Using electrophysiology, immunocytochemistry, and molecular biological approaches, this study investigated the role of AChE in the regulation of synaptic formation and functions. We found that AChE was highly expressed in cultured embryonic hippocampal neurons at early culture days, particularly in dendritic compartments including the growth cone. Subsequently, the expression level of AChE declined, whereas synaptic activity and synaptic proteins progressively increased. Chronic blockade of the PAS of AChE with specific inhibitors selectively impaired glutamatergic functions and excitatory synaptic structures independently of cholinergic activation, while inducing AChE overexpression. Moreover, the PAS blockade-induced glutamatergic impairments were associated with a depressed expression of ␤-neurexins and an accumulation of other synaptic proteins, including neuroligins, and were mostly preventable by antisense suppression of AChE expression. Our findings demonstrate that interference with the nonenzymatic features of AChE alters AChE expression, which impairs excitatory synaptic structure and functions.

show abstract

Complex Host Cell Responses to Antisense Suppression ofACHEGene Expression

Cited by 21 publications

References 25 publications

RNA-Targeted Suppression of Stress-Induced Allostasis in Primate Spinal Cord Neurons

RNA-Targeted Suppression of Stress-Induced Allostasis in Primate Spinal Cord Neurons

Peripheral Site Acetylcholinesterase Blockade Induces RACK1-Associated Neuronal Remodeling

Excessive Expression of Acetylcholinesterase Impairs Glutamatergic Synaptogenesis in Hippocampal Neurons

Contact Info

Product

Resources

About