Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0234238 (ACHE)
 235 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anxiety involves complex, incompletely understood interactions of genomic, environmental, and experience-derived factors, and is currently being measured by psychological criteria. Here, we report previously nonperceived interrelationships between expression variations and nucleotide polymorphisms of the chromosome 7q21-22 acetylcholinesterase-paraoxonase 1 (ACHE-PON1) locus with the trait- and state-anxiety measures of 461 healthy subjects from the Health, Risk Factors, Exercise Training, and Genetics Family Study. The AChE protein controls the termination of the stress-enhanced acetylcholine signaling, whereas the PON protein displays peroxidase-like activity, thus protecting blood proteins from oxidative stress damages. Serum AChE and PON enzyme activities were both found to be affected by demographic parameters, and showed inverse, reciprocal associations with anxiety measures. Moreover, the transient scores of state anxiety and the susceptibility score of trait anxiety both appeared to be linked to enzyme activities. This finding supported the notion of corresponding gene expression relationships. Parallel polymorphisms in the ACHE and PON1 genes displayed apparent associations with both trait- and state-anxiety scores. Our findings indicate that a significant source of anxiety feelings involves inherited and acquired parameters of acetylcholine regulation that can be readily quantified, which can help explaining part of the human variance for state and trait anxiety.
 ...
PMID:Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in Health, Risk Factors, Exercise Training, and Genetics study. 1506 Feb 81

Exposure to agricultural insecticides, together with yet incompletely understood predisposing genotype/phenotype elements, notably increase the risk of Parkinson's disease. Here, we report findings attributing the increased risk in an insecticide-exposed rural area in Israel to interacting debilitating polymorphisms in the ACHE/PON1 locus and corresponding expression variations. Polymorphisms that debilitate PON1 activity and cause impaired AChE overproduction under anticholinesterase exposure were strongly overrepresented in patients from agriculturally exposed areas, indicating that they confer risk of Parkinson's disease. Supporting this notion, serum AChE and PON1 activities were both selectively and significantly lower in patients than in healthy individuals and in carriers of the risky polymorphisms as compared with other Parkinsonian patients. Our findings suggest that inherited interactive weakness of AChE and PON1 expression increases the insecticide-induced occurrence of Parkinson's disease.
 ...
PMID:Acetylcholinesterase/paraoxonase interactions increase the risk of insecticide-induced Parkinson's disease. 1562 87

The 5.5 Mb chromosome 7q21-22 ACHE/PON1 locus harbours the ACHE gene encoding the acetylcholine hydrolyzing, organophosphate (OP)-inhibitable acetylcholinesterase protein and the paraoxonase gene PON1, yielding the OP-hydrolyzing PON1 enzyme which also displays arylesterase activity. In search of inherited and acquired ACHE-PON1 interactions we genotyped seven polymorphic sites and determined the hydrolytic activities of the corresponding plasma enzymes and of the AChE-homologous butyrylcholinesetrase (BChE) in 157 healthy Israelis. AChE, arylesterase, BChE and paraoxonase activities in plasma displayed 5.4-, 6.5-, 7.2- and 15.5-fold variability, respectively, with genotype-specific differences between carriers of distinct compound polymorphisms. AChE, BChE and arylesterase but not paraoxonase activity increased with age, depending on leucine at PON1 position 55. In contrast, carriers of PON1 M55 displayed decreased arylesterase activity independent of the - 108 promoter polymorphism. Predicted structural consequences of the PON1 L55M substitution demonstrated spatial shifts in adjacent residues. Molecular modelling showed substrate interactions with the enzyme variants, explaining the changes in substrate specificity induced by the Q192R substitution. Intriguingly, PON1, but not BChE or arylesterase, activities displayed inverse association with AChE activity. Our findings demonstrate that polymorphism(s) in the adjacent PON1 and ACHE genes affect each other's expression, predicting for carriers of biochemically debilitating ACHE/PON1 polymorphisms adverse genome-environment interactions.
 ...
PMID:Inherited and acquired interactions between ACHE and PON1 polymorphisms modulate plasma acetylcholinesterase and paraoxonase activities. 1571 71

Much has been learned in recent years about the genetics of familial Parkinson's disease. However, far less is known about those malfunctioning genes which contribute to the emergence and/or progression of the vast majority of cases, the 'sporadic Parkinson's disease', which is the focus of our current review. Drastic differences in the reported prevalence of Parkinson's disease in different continents and countries suggest ethnic and/or environmental-associated multigenic contributions to this disease. Numerous association studies showing variable involvement of multiple tested genes in these distinct locations support this notion. Also, variable increases in the risk of Parkinson's disease due to exposure to agricultural insecticides indicate complex gene-environment interactions, especially when genes involved in protection from oxidative stress are explored. Further consideration of the brain regions damaged in Parkinson's disease points at the age-vulnerable cholinergic-dopaminergic balance as being involved in the emergence of sporadic Parkinson's disease in general and in the exposure-induced risks in particular. More specifically, the chromosome 7 ACHE/PON1 locus emerges as a key region controlling this sensitive balance, and animal model experiments are compatible with this concept. Future progress in the understanding of the genetics of sporadic Parkinson's disease depends on globally coordinated, multileveled studies of gene-environment interactions.
 ...
PMID:Gene-environment interactions in sporadic Parkinson's disease. 1680 80

Organophosphate pesticides (OPs), known inhibitors of acetylcholinesterase (AChE), are used extensively throughout the world. Recent studies have focused on the ACHE/PON1 locus as a determinant of inherited susceptibility to environmental OP exposure. To explore the relationship of the corresponding gene-environment interactions with brain activity, we integrated neurophysiologic, neuropsychological, biochemical, and genetic methods. Importantly, we found that subthreshold OP exposure leads to discernible physiological consequences that are significantly influenced by inherited factors. Cortical EEG analyses by LORETA revealed significantly decreased theta activity in the hippocampus, parahippocampal regions, and the cingulate cortex, as well as increased beta activity in the prefrontal cortex of exposed individuals-areas known to play a role in cholinergic-associated cognitive functions. Through neuropsychological testing, we identified an appreciable deficit in the visual recall in exposed individuals. Other neuropsychological tests revealed no significant differences between exposed and non-exposed individuals, attesting to the specificity of our findings. Biochemical analyses of blood samples revealed increases in paraoxonase and arylesterase activities and reduced serum acetylcholinesterase activity in chronically exposed individuals. Notably, specific paraoxonase genotypes were found to be associated with these exposure-related changes in blood enzyme activities and abnormal EEG patterns. Thus, gene-environment interactions involving the ACHE/PON1 locus may be causally involved in determining the physiological response to OP exposure.
 ...
PMID:Coding region paraoxonase polymorphisms dictate accentuated neuronal reactions in chronic, sub-threshold pesticide exposure. 1680 70