On novel functions of cholinesterases

• Main Author: Allebrandt, Karla Viviani
• Format: Others
• Language: English; en
• Published: 2006
• Online Access: http://tuprints.ulb.tu-darmstadt.de/644/1/AllebrandtDissertation.pdf; Allebrandt, Karla Viviani <http://tuprints.ulb.tu-darmstadt.de/view/person/Allebrandt=3AKarla_Viviani=3A=3A.html> : On novel functions of cholinesterases. [Online-Edition] Technische Universität, Darmstadt [Ph.D. Thesis], (2006)

The non-specificity of cholinesterases to cholinergic innervated tissues, their early onset during embryogenesis of many organisms, and their non-cholinolytic aryl acylamidase activity, indicate that these enzymes are involved with physiological processes other than the termination of nervous impulse. In this study, cholinesterases expression and function were investigated during the development of two model organisms, chicken (Gallus gallus) and zebrafish (Danio rerio), with the focus on non-cholinolytic and non-catalytic events. In chicken, the pineal organ was investigated taking into consideration: a) its similarity to the eye, as earlier studies suggested a relevance of cholinesterases to retina embryogenesis, b) its relevance on controlling physiological functions following a circadian rhythm, and c) its disfunction in pathological states, which also present altered cholinesterases expression, like Alzheimer’s disease. Indeed, in this study, a remarkable developmentally regulated switch from butyrylcholinesterase (BChE) to acetylcholinesterase (AChE) expression during pineal embryogenesis was found, in association with cell proliferation and differentiation, respectively. Even more, AChE-positive cells were shown to guide the pineal epithelium remodeling (leading to follicles development), indicating it plays a pivotal role in pineal embryogenesis. Besides, the appearance of follicular supportive cells correlated with this remodeling onset, followed by photoreceptor cells differentiation, indicating that these events are interconnected. Furthermore, AChE was demonstrated to be active in cells undergoing apoptosis during pineal embryogenesis, corroborating earlier in vitro studies indicating its involvement with the apoptotic process. However, the mechanism of action of cholinesterases in most of these developmental events is not clear, in particular whether the function could be structural or non-cholinolytic. Using zebrafish as a second model organism, a non-cholinolytic activity of AChE was investigated, from the time its transcription begins until larval development of this organism. This study revealed a particular profile of the AChE-associated aryl acylamidase activity (AAA) during development of zebrafish. AAA was particularly more pronounced than the esterase activity during zebrafish embryogenesis, indicating a relevance of this activity during early development. This non-cholinolytic activity was further investigated in human recombinant BChE wild-type and mutant proteins to address its catalytic power in enzymes with low cholinergic functionality. Altogether, these three studies on novel functions of cholinesterases address aspects of these enzymes also in relation to serotonin, as follow: a) cholinesterases are implicated in the development of the pineal gland, an organ controlling serotonin metabolism; b) a temporal high sensitivity of zebrafish embryos towards serotonin administration correlated with AChE expression onset during their blastula period, and c) serotonin directly interacts with cholinesterases, demonstrated through a non-competitive inhibition of the AAA activity on purified recombinant human BChE. This PhD work, therefore, presents strong evidence of the AChE involvement with morphogenesis, with further implications of its expression for pineal cells differentiation and apoptosis. It also writes further history on the little investigated side activity of cholinesterases, the aryl acylamidase, and supports a link between cholinergic and serotonergic systems.