Virtues and woes of AChE alternative splicing in stress-related neuropathologies

doi:10.1016/j.tins.2006.02.005

Trends in Neurosciences

Volume 29, Issue 4, April 2006, Pages 216-224

https://doi.org/10.1016/j.tins.2006.02.005 Get rights and content

The ACh hydrolyzing enzyme acetylcholinesterase (AChE) is a combinatorial series of proteins with variant N and C termini generated from alternate promoter usage and 3′ alternative splicing. Neuronal AChE variants show indistinguishable enzymatic activity yet differ in their expression, multimeric assembly and membrane-association patterns. Differentially induced under stress, they show distinct non-hydrolytic properties and interact with different protein partners. Recent findings suggest that transcriptional and post-transcriptional regulation of AChE pre-mRNA is a neuroprotection strategy but might involve long-term damage. Specifically, variant-specific causal involvement of AChE in the progression of both neurodegenerative diseases (e.g. Alzheimer's and Parkinson's diseases) and neuromuscular syndromes (e.g. myasthenia gravis) raises the possibility that future therapeutic drugs might target specific AChE variant(s) or the corresponding RNA transcripts.

Section snippets

The composition and role of AChE

Much has been learned and said about both the hydrolytic and the non-catalytic roles of acetylcholinesterase (AChE) 1, 2, 3. Its primary role undoubtedly remains that of hydrolyzing synaptic ACh. In this role, AChE is one of the most efficient enzymes in nature, capable of hydrolyzing ACh at a rate so high that it is limited only by diffusion [4]. This property makes it evolutionarily an almost perfect terminator of ACh-mediated neurotransmission. The discovery that AChE knockout mice were born

AChE in stress-related neurological disorders

Transcriptional and post-transcriptional stress-related responses interact to induce a cascade of changes in the levels and properties of brain proteins that might be involved in neuronal reactions to stimuli [16]. Proteins involved in stress-related neurotransmission pathways are particularly affected in this way. ACh levels are transiently elevated in the mammalian brain during stress responses [17], and similar increases in ACh-mediated signaling have been reported following exposure to

AChE variants in Alzheimer's disease, Parkinson's disease and myasthenia gravis

Alzheimer's disease (AD), Parkinson's disease (PD) and myasthenia gravis (MG) are the three best-studied neuropathologies associated with AChE alterations. AD is the most prevalent type of dementia in the elderly and is characterized by deposition of β-amyloid protein, which is processed by proteolytic cleavage of the β-amyloid protein precursor [41]. Forming of these deposits or plaques is characteristic of the early pathogenesis in AD. Cholinergic circuits are supposedly not impaired until

Stress-induced changes in neuronal alternative splicing

Splicing aberrations have been reported in many diseases [49] and in aging [50], but the underlying molecular mechanism remains largely obscure. How does stress trigger alternative splicing of neuronal AChE and accumulation of AChE-R? To address this question, one should examine the combined consequences of stress on constitutive splicing (Box 2), alternative splicing and splicing factors.

Various stressful stimuli involve regulated, specific modulations in neuronal alternative splicing [51].

Concluding remarks and future perspectives

The variety of AChE alternative transcripts highlights AChE as a complex molecule with a tightly regulated pattern of expression. The uniqueness of each variant is accentuated by its expression timing (e.g. during health or disease, or during normal or stressful situations), its expression compartment (e.g. in neurites or on synaptic membranes) and its interaction partners (e.g. PRiMA, GPI and RACK1). These three factors add an extra dimension to the intricate control of variant AChE proteins.

Acknowledgements

Our work is supported by the Israel Science Foundation 618-02-1, the European Community LSHM-CT-2003–503330 and European Alternative Splicing Network of Excellence- LSH-2004-1.1.5-3, the German–Israeli-Foundation (Grant 673), and Ester Neuroscience.

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Trends in Neurosciences

Virtues and woes of AChE alternative splicing in stress-related neuropathologies

Section snippets

The composition and role of AChE

AChE in stress-related neurological disorders

AChE variants in Alzheimer's disease, Parkinson's disease and myasthenia gravis

Stress-induced changes in neuronal alternative splicing

Concluding remarks and future perspectives

Acknowledgements

Curr. Opin. Pharmacol.

Neuron

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Trends Neurosci.

Neuron

Brain Behav. Immun.

FEBS Lett.

Pharmacol. Res.

Toxicol. Lett.

Brain Res.

Brain Res.

Neuropharmacology

Neuroscience

Cell

J. Biol. Chem.

Acetylcholinesterase – new roles for an old actor

Nat. Rev. Neurosci.

Are there non-catalytic functions of acetylcholinesterases? Lessons from mutant animal models

BioEssays

Acetylcholinesterase: enzyme structure, reaction dynamics, and virtual transition states

Chem. Rev.

Acetylcholinesterase is required for neuronal and muscular development in the zebrafish embryo

Nat. Neurosci.

Postnatal developmental delay and supersensitivity to organophosphate in gene-targeted mice lacking acetylcholinesterase

J. Pharmacol. Exp. Ther.

Neurobiology of butyrylcholinesterase

Nat. Rev. Neurosci.

Acute stress facilitates long-lasting changes in cholinergic gene expression

Nature

Alternative splicing and neuritic mRNA translocation under long-term neuronal hypersensitivity

Science

Developmental regulation of acetylcholinesterase transcripts in the mouse diaphragm: alternative splicing and focalization

Eur. J. Neurosci.

The origin of the molecular diversity and functional anchoring of cholinesterases

Neurosignals

The cholinesterases: from genes to proteins

Annu. Rev. Pharmacol. Toxicol.

COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression

Proc. Natl. Acad. Sci. U. S. A.

Stress and plasticity in the limbic system

Neurochem. Res.

Effect of treatment with the cholinesterase inhibitor rivastigmine on vesicular acetylcholine transporter and choline acetyltransferase in rat brain

Clin. Exp. Hypertens.

Excess ‘read-through’ acetylcholinesterase attenuates but the ‘synaptic’ variant intensifies neurodeterioration correlates

Proc. Natl. Acad. Sci. U. S. A.

The role of readthrough acetylcholinesterase in the pathophysiology of myasthenia gravis

FASEB J.

Chronic cholinergic imbalances promote brain diffusion and transport abnormalities

FASEB J.

Neuronal overexpression of ‘readthrough’ acetylcholinesterase is associated with antisense-suppressible behavioral impairments

Mol. Psychiatry

The readthrough variant of acetylcholinesterase remains very minor after heat shock, organophosphate inhibition and stress, in cell culture and in vivo

J. Neurochem.