Synaptogenesis and myopathy under acetylcholinesterase overexpression.
Environmental, congenital, and acquired immunological insults perturbing neuromuscular junction (NMJ) activity may induce a variety of debilitating neuromuscular pathologies. However, the molecular elements linking NMJ dysfunction to long-term myopathies are unknown. Here, we report dramatically elevated levels of mRNA encoding c-Fos and the "readthrough" (R) variant of acetylcholinesterase (AChE) in muscles of transgenic mice overexpressing synaptic (S) AChE in motoneurons and in control mice treated with the irreversible cholinesterase inhibitor diisopropylfluorophosphonate (DFP). Tongue muscles from DFP-treated and AChE-S transgenic mice displayed exaggerated neurite branching and disorganized, wasting fibers. Moreover, diaphragm muscles from both transgenic and DFP-treated mice exhibited NMJ proliferation. 2'-O-methyl-protected antisense oligonucleotides targeted to AChE mRNA suppressed feedback upregulation of AChE and ameliorated DFP-induced NMJ proliferation. Our findings demonstrate common transcriptional responses to cholinergic NMJ stress of diverse origin, and implicate deregulated AChE expression in excessive neurite outgrowth, uncontrolled synaptogenesis, and myopathology.
Lev-Lehman
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Department of Biological Chemistry, The Life Sciences Institute, The Hebrew University of Jerusalem, Israel.
Evron
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Broide
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Meshorer
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Ariel
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Seidman
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Soreq
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D000110:Acetylcholinesterase / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D017931:DNA Primers; D005091:Exons; D005786:Gene Expression Regulation; D016762:Genes, fos; D014644:Genetic Variation; D007531:Isoflurophate / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000201:enzymology; D018482:Muscle, Skeletal / Q000473:pathology*; D009469:Neuromuscular Junction / Q000473:pathology*; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013569:Synapses / Q000473:pathology* / Q000502:physiology; D014059:Tongue / Q000201:enzymology; D014158:Transcription, Genetic
D002800:Cholinesterase Inhibitors; D017931:DNA Primers; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D007531:Isoflurophate; D000110:Acetylcholinesterase