Acetylcholinesterase deficiency

Engek A. G., Lambert, E H.. and Gomez. M. R. (1977). A new myasthenic syndrome with end-plate acetylcholinesterase deficiency, small nerve terminals, and reduced acetylcholine release. Ann. Neurol. 1, 315-330. 

Ohno, K-, Brcngman, L M., Tsujino, A., and Engd, A, G. (1998). Human endplate acetylcholinesterase deficiency caused by mutations in the collageii-like tail subunit (ColQ) of the asymmetric enzyme. Proc. Natl. Acad. Sci. USA 95,96,54-9659. 

The only known change in neurotransmitter metabolism so far detected is a deficiency of acetylcholine in the brain. This has been shown in post-mortem studies on the brains of patients with Alzheimer s disease. Some success in reducing the symptoms of the disease has been obtained with drugs that inhibit the activity of acetylcholinesterase leading to an increase in the acetylcholine concentration, but the improvement is minimal so that its use is controversial. 

The devastating mental deterioration that characterizes Alzheimer s disease has been attributed to a mishandling of the neurotransmitter acetylchohne. Inhibitors of acetylcholinesterase, the enzyme that catabolizes that substance, would be expected to help restore deficient acetylcholine levels. Several partly reduced acridines have shown some activity in treating Alzheimer s disease. At least one of these, tacrine (14-5), is now approved for use in patients. The initial step in the synthesis of the first of these consists of the sodium amide catalyzed condensation of isatin (14-1) with cyclohexanone. The reaction can be visualized by assuming the first step to involve an attack of amide on isatin to give an amido-amide such as (14-2) (note that no attempt has been made to account for charges). This can then react with... 

Schober, A., Minichiello, L., Keller, M., Huber, K., Layer, P.G., Roig-Lopez, J.L., Garcia-Arraras, J.E., Klein, R., Unsicker, K. (1997). Reduced acetylcholinesterase (AChE) activity in adrenal medulla and loss of sympathetic preganglionic neurons in TrkA-deficient, but not TrkB-deficient, mice. J. Neurosci. 17 891-903. 

Pseudocholinesterase deficiency. The neuromuscular blocking action of suxamethonium is terminated by plasma pseudocholinesterase. True cholinesterase (acetylcholinesterase) hydrolyses acetylcholine released by nerve endings, whereas various tissues and plasma contain other nonspecific, hence pseudo, esterases. Affected individuals form so little plasma pseudocholinesterase that metabolism of suxamethonium is seriously reduced. The deficiency characteristically comes to light when a patient fails to breathe spontaneously after a surgical operation, and assisted ventilation may have to be undertaken for hours. Relatives of an affected individual—for this as for other inherited abnormalities carrying avoidable risk—should be sought out, checked to assess their own risk, and told of the result. The prevalence of pseudocholinesterase deficiency in the UK population is about 1 in 2500. 

Donepezil is a cholinesterase inhibitor which increases acetylcholine by inhibiting acetylcholinesterase, thereby increasing cholinergic function. It is indicated in the treatment of mild to moderate dementia of the Alzheimer type. A deficiency of intact cholinergic neurons, particularly those extending from subcortical areas such as the nucleus basalis of Meynert, has been observed in patients with... 

A review of the literature of the distribution, function and structure of acetylcholinesterase is too voluminous for the scope of this article, and the reader is referred elsewhere [1]. Cholinesterase enzyme is a protein, and a dietary deficiency of protein can result in lower cholinesterase activity in liver microsomes and serum of rats. Cholinesterase inhibition by parathion and by Banol (6-chloro-3,4-xylyl methylcarbamate) (Upjohn) is more at lower dietary levels of casein than at higher levels, thus confirming that the toxicity of these enzyme inhibitors is greater at lower dietary protein levels [13]. This observation indicates that a causal relationship exists between amino-acid intake and cholinesterase activity. 

Furthermore, in vitro classical homocystinuria showed an elevation of rat hippocampal acetylcholinesterase (AChE) activity, whereas the other types of homocystinuria had no effect on the enzyme (Schulpis et al., 2006). These preliminary results may lead to the suggestion that homocystinuria due to cystathionine-6-synthase deficiency may partly implicate high Hey levels with neurodegeneration. 

Fig. 1. Effect of F on the acetylcholinesterase from rats fed a fat-sufficient ( - ) and a fat-deficient (o-o) diet. Insert Hill plot.

The electrophorectic patterns of acetylcholinesterase (solubilized by different agents such as Triton X-100 at different concentrations, sodium deoxycholate or ultrasonic irradiation) indicated the presence of multiple enz)nnatic forms, the chemical nature of which are only partially understood. However, the multiple forms for either the enzyme from the sufficient or deficient animals, respectively, were not significantly different (Martinez de Melian et al., 1976). These results are presented in Table 1. A single band of activity in polyacrylamide-gel, independent upon the method employed, can be obtained under controlled and standard conditions. 

In Table 2, the values of n are presented for the intact membrane, solubilized membrane, reaggregated material and Triton X-100 solubilized reaggregated material from animals fed corn oil supplemented diet and fat-free diet, respectively. As it can be observed, the value of n is around 1.6 for all the enzyme preparations from the fat sufficient animals. For the preparations from the fat deficient animals instead it is in the order of 1.0 in the case of intact membrane and reaggregation membrane like material, and around 1.6 for the solubilized preparations. Similar results were obtained with the other solubilizing agents (Martinez de Melian et al., 1976). Further evidence on the role played by the membrane was obtained when the acetylcholinesterase band from the gel electrophoresis of solubilized acetylcholinesterase from fat sufficient animals was eluted, mixed with lipid extracted from red cell membranes of rat fed a fat-free diet, and diffused against buffer. A value of n=1.0, which corresponds to that of the intact membrane from the deficient... 

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