From Protein to Peptides: a Spectrum of Non-Hydrolytic Functions of Acetylcholinesterase

Abstract

Acetylcholinesterase (AChE), a member of the α/β-hydrolase fold superfamily of proteins, is a serine hydrolase responsible for the hydrolysis of the well studied neurotransmitter acetylcholine (ACh). However, it is becoming clear that AChE has a range of actions other than this 'classical' role. Non-classical AChE functions have been identified in apoptosis, stress-responses, neuritogenesis, and neurodegeneration. Furthermore, these non-classical roles are attributable not only to the native protein, which appears to act as a mediary binding protein under a number of circumstances, but also to peptides cleaved from the parent protein. Peptides cleaved from AChE can act as independent signalling molecules. Here we discuss the implications of non-hydrolytic functions of this multi-tasking protein.

Presymptomatic Treatment with Acetylcholinesterase Antisense Oligonucleotides Prolongs Survival in ALS (G93A-SOD1) Mice

“…Based on the circumstantial evidence linking AChE to ALS pathogenesis we sought to test the possibility that downregulation of AChE may be beneficial in an ALS mouse model. Because AChE may have noncatalytic effects [8, 9] together with the fact that AChE inhibition with drugs such as neostigmine (Neo) raise AChE levels [10], we chose to use antisense oligonucleotides (ASO) to AChE mRNA (mEN101) as our treatment drug. To address the possibility that mEN101's effect is mediated via a non-catalytic effect (i.e., reducing AChE levels) rather than via a decrease in catalytic activity, we compared mEN101 treatment to the AChE catalytic inhibitor Neo.…”

Ontogenetic and Phylogenetic Approaches for Studying the Mechanisms of Cognitive Dysfunctions

“…Thus, in postnatal ontogenesis of hypoxic rats, the activity of acetyl-and butyrylcholinesterases (AChE and BChE) in the sensorimotor cortex had a significantly different dynamics compared to controls [68]. Apart from decreased activity of these enzymes during the first month of postnatal ontogenesis (and active formation of synaptic contacts), there were also significant changes in the distribution of the membrane-bound (involved in signal transduction) and soluble (participating in synaptogenesis [69]) forms of AChE. Moreover, with aging in rats subjected to prenatal hypoxia, there was an increase in the ratio of BChE in the total cholinesterase activity that could have a compensatory nature since this enzyme plays an important role in hydrolyzing various toxic agents, which might be produced by impaired brain tissue.…”

Acetylcholinesterases of blood-feeding flies and ticks

“…In addition to the canonical role in termination of neural impulses by catalytic hydrolysis of acetylcholine, AChE in vertebrates is postulated to play many additional roles in physiology and development [35,36]. The presence of multiple genes encoding AChE in ticks may provide separation of structure and function (see Fig.…”