Abstract:Acetylcholinesterase (AChE) plays a crucial physiological role in termination of impulse transmission at cholinergic synapses through rapid hydrolysis of acetylcholine. It is a highly conserved molecule, and only a few naturally occurring genetic polymorphisms have been reported in the human gene. The goal of the present study was to make a systematic effort to identify natural single nucleotide polymorphisms (SNPs) in the human ACHE gene. To this end, the genomic coding sequences for acetylcholinesterase of 9… Show more
“…The 3′UTR C2098A substitution (rs17228616) is located in the ‘seed’-interacting region of a putative AChE-binding site to miR-608 (18,21), close to the binding site of the AChE-targeting miR-132 (4) (Fig. 1B and C).…”
Section: Resultsmentioning
confidence: 99%
“…1A). Therefore, we used this case to test the impact of the AChE 3′UTR rs17228616 SNP (18) () located at the AChE-binding site with the primate-specific miR-608 on its interactions with the validated CDC42 (19) and interleukin-6 (IL6) (20) targets in vitro and in vivo and the consequences of changes in these interactions. Figure 1.miR-608 targets the major rs17228616 AChE allele.…”
MicroRNAs (miRNAs) can repress multiple targets, but how a single de-balanced interaction affects others remained unclear. We found that changing a single miRNA–target interaction can simultaneously affect multiple other miRNA–target interactions and modify physiological phenotype. We show that miR-608 targets acetylcholinesterase (AChE) and demonstrate weakened miR-608 interaction with the rs17228616 AChE allele having a single-nucleotide polymorphism (SNP) in the 3′-untranslated region (3′UTR). In cultured cells, this weakened interaction potentiated miR-608-mediated suppression of other targets, including CDC42 and interleukin-6 (IL6). Postmortem human cortices homozygote for the minor rs17228616 allele showed AChE elevation and CDC42/IL6 decreases compared with major allele homozygotes. Additionally, minor allele heterozygote and homozygote subjects showed reduced cortisol and elevated blood pressure, predicting risk of anxiety and hypertension. Parallel suppression of the conserved brain CDC42 activity by intracerebroventricular ML141 injection caused acute anxiety in mice. We demonstrate that SNPs in miRNA-binding regions could cause expanded downstream effects changing important biological pathways.
“…The 3′UTR C2098A substitution (rs17228616) is located in the ‘seed’-interacting region of a putative AChE-binding site to miR-608 (18,21), close to the binding site of the AChE-targeting miR-132 (4) (Fig. 1B and C).…”
Section: Resultsmentioning
confidence: 99%
“…1A). Therefore, we used this case to test the impact of the AChE 3′UTR rs17228616 SNP (18) () located at the AChE-binding site with the primate-specific miR-608 on its interactions with the validated CDC42 (19) and interleukin-6 (IL6) (20) targets in vitro and in vivo and the consequences of changes in these interactions. Figure 1.miR-608 targets the major rs17228616 AChE allele.…”
MicroRNAs (miRNAs) can repress multiple targets, but how a single de-balanced interaction affects others remained unclear. We found that changing a single miRNA–target interaction can simultaneously affect multiple other miRNA–target interactions and modify physiological phenotype. We show that miR-608 targets acetylcholinesterase (AChE) and demonstrate weakened miR-608 interaction with the rs17228616 AChE allele having a single-nucleotide polymorphism (SNP) in the 3′-untranslated region (3′UTR). In cultured cells, this weakened interaction potentiated miR-608-mediated suppression of other targets, including CDC42 and interleukin-6 (IL6). Postmortem human cortices homozygote for the minor rs17228616 allele showed AChE elevation and CDC42/IL6 decreases compared with major allele homozygotes. Additionally, minor allele heterozygote and homozygote subjects showed reduced cortisol and elevated blood pressure, predicting risk of anxiety and hypertension. Parallel suppression of the conserved brain CDC42 activity by intracerebroventricular ML141 injection caused acute anxiety in mice. We demonstrate that SNPs in miRNA-binding regions could cause expanded downstream effects changing important biological pathways.
“…A study on the ACHE gene in African Americans, Israeli Arabs and Ashkenazi and Sephardic Jews showed 13 SNPs of which five lead to amino acid substitutions that are either absent from the mature protein or reside far from the active site of acetylcholinesterase and should not have a direct impact on its catalytic properties [33]. Considering mutations in exons 2 and 4 that lead to amino acid substitution in the mature BChE (Table 1), only the A539T variant is very frequent and three others have frequencies near 1%.…”
Human butyrylcholinesterase (BChE; EC 3.1.1.8) is codified by the BCHE gene (3q26.1-q26.2) in which 65 variants have been identified. BChE is a scavenger of organophosphorus and carbamate compounds and hydrolyzes succinylcholine, mivacurium and cocaine. The present study describes 12 naturally occurring BCHE mutations including five new mutations (K12R, G15G, V294M, G333C and R470W) identified in 366 blood donors from Southern Brazil. Exons 2 and 4 of the BCHE gene were examined by PCR-SSCA and samples with unexpected electrophoretic patterns were sequenced. The respective nucleotide substitution that characterizes each of the four new nonsynonymous mutations was introduced into BCHE cDNA by site directed mutagenesis and transfected into human embryonic kidney 293T cells and/or Chinese hamster ovary cells. The catalyzed hydrolysis of butyrylthiocholine (BTC) by BChE was measured by the Ellman method. Enzyme kinetic parameters obtained after the expression of the respective recombinant BChE evaluated the effects of the four nonsynonymous mutations. Thirty-four out of 366 individuals carried a BChE mutation in exon 2. The K variant mutation, A539T in exon 4, was present in one out of three persons. Gene expression showed that only one of the newly identified mutations (G333C) altered BChE activity, leading to a decrease of about 80% in relation to the wild-type enzyme.
“…It also suggests that the pathophysiology underlying the different subtypes of delirium may be different. Differences in AChE enzyme activity can be explained by genetic causes that could underlie differences in AChE activity according to distinct alleles [35] or single-nucleotide polymorphisms [36]. This has been documented for butylcholinesterase [37], another non-specific cholinesterase found in humans.…”
Aims: Cholinergic deficiency is commonly implicated in the pathophysiology of delirium. We aimed to investigate the relationship between directly measured serum acetylcholinesterase (AChE) activity and (1) clinical features of delirium and (2) outcomes among older hospital patients with delirium. Methods: Hospitalised patients with delirium were recruited, and delirium motor subtype, severity and duration of delirium were measured. Serum AChE activity was measured using a colorimetric assay. Results: The mean AChE activity for the whole sample was 2.46 μmol/μL/min (standard deviation 1.75). Higher AChE activity was associated with increased likelihood of hypoactive delirium rather than the hyperactive or mixed subtype (odds ratio 1.98, 95% confidence interval 1.10-3.59). Conclusion: Higher AChE activity was associated with hypoactive delirium but did not predict outcomes. Simple enhancement of cholinergic neurotransmission may not be sufficient to treat delirium.
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