Cholinotoxic effects on acetylcholinesterase gene expression are associated with brain-region specific alterations in G,C-rich transcripts.
To study the mechanisms underlying cholinotoxic brain damage, we examined ethylcholine aziridinium (AF64A) effects on cholinesterase genes. In vitro, AF64A hardly affected cholinesterase activities yet inhibited transcription of the G,C-rich AChE DNA encoding acetylcholinesterase (AChE) more than the A,T-rich butyrylcholinesterase (BChE) DNA. In vivo, intracerebroventricular injection of 2 nmol of AF64A decreased AChE mRNA in striatum and septum by 3- and 25-fold by day 7, with no change in BChE mRNA or AChE activity. In contrast, hippocampal AChE mRNA increased 10-fold by day 7 and BChE mRNA and AChE activity decreased 2-fold. By day 60 post-treatment, both AChE mRNA and AChE levels returned to normal in all regions except hippocampus, where AChE activity and BChE mRNA were decreased by 2-fold. Moreover, differential PCR displays revealed persistent induction, specific to the hippocampus of treated rats, of several unidentified G,C-rich transcripts, suggesting particular responsiveness of hippocampal G,C-rich genes to cholinotoxicity.
Department of Biological Chemistry, Life Sciences Institute, Hebrew University, Jerusalem, Israel.
E
E
Lev-Lehman
A
A
el-Tamer
A
A
Yaron
M
M
Grifman
D
D
Ginzberg
I
I
Hanin
H
H
Soreq
D000110:Acetylcholinesterase / Q000096:biosynthesis*; D000704:Analysis of Variance; D000818:Animals; D001388:Aziridines / Q000008:administration & dosage / Q000494:pharmacology*; D001483:Base Sequence; D001921:Brain / Q000201:enzymology*; D002091:Butyrylcholinesterase / Q000096:biosynthesis*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D002794:Choline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D017931:DNA Primers; D015870:Gene Expression / Q000187:drug effects*; D007276:Injections, Intraventricular; D008297:Male; D008969:Molecular Sequence Data; D009466:Neuromuscular Blocking Agents / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
D001388:Aziridines; D017931:DNA Primers; D009466:Neuromuscular Blocking Agents; D012333:RNA, Messenger; C044894:ethylcholine aziridinium; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002794:Choline