ACHE (acetylcholinesterase)

2012-05-01   Hermona Soreq , David S Greenberg 

Department of Biological Chemistry, the Edmond, Lily Safra Center of Neuroscience, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel

Identity

HGNC
LOCATION
7q22.1
LOCUSID
ALIAS
ACEE,ARACHE,N-ACHE,YT
FUSION GENES

DNA/RNA

Atlas Image
The human AChE gene is located at q22 of the long arm of chromosome 7. The AChE mRNA has multiple isoforms which arise from both alternative promoter usage in the 5 of the gene and alternative splicing of exons 4, 5 and 6.

Description

The ACHE gene spans about 6 kilobases on chromosome 7q22.

Transcription

The gene gives rise to multiple alternatively spliced transcripts. These include AChE-Synaptic (AChE-S), AChE-Erythrocyte (AChE-E) and AChE-Read through (AChE-R). AChE-S is the major neuronal transcript. Alternative 3 splicing gives rise to AChE-E, a dimeric glycophosphatidylinositol (GPI)-anchored isoform expressed primarily in erythrocytes. The third variant AChE-R is produced by the inclusion of the normally spliced out intron 4 and is reported to be elevated during stress. In addition, the existence of multiple promoters leads to the production of several variants with extended N-terminal sequences which are transcribed from the alternative promoters although their expression patterns have not yet been well characterized (Soreq and Seidman, 2001; Meshorer and Soreq, 2006).

Pseudogene

None.

Proteins

Description

Acetylcholinesterase (AChE) is a 57 kDa protein. AChE can be monomeric (AChE-R), dimeric (AChE-E) or tetrameric (AChE-S). Tetrameric AChE-S can further interact with collagen Q (ColQ), enabling anchorage to neuromuscular junctions (NMJs), and a proline-rich membrane anchor protein (PRiMA) is responsible for the synaptic docking of AChE-S in the brain. AChE-R is a soluble monomer with a unique naturally unfolded C-terminal peptide. Because AChE-E and AChE-R are incapable of anchorage to the NMJ or to synaptic membranes through ColQ or PRiMA, only the AChE-S form of the enzyme is regarded as truly "synaptic" (Massoulié et al., 1993; Taylor et al., 1993; Silman and Sussman, 2008).

Expression

Functional heterogeneity in AChE activity is regulated at the transcriptional, post-transcriptional and post-translational levels, leading to complex expression patterns that reflect tissue and cell-type specificity, differentiation state, physiological condition and response to external stimuli. Recent studies have also looked at regulation of AChE expression by microRNA (Hanin and Soreq, 2011).

Localisation

Intracellular, extracellular, plasma, cerebrospinal fluid.

Function

Acetylcholinesterase is a type B hydrolase that rapidly and selectively hydrolyzes the neurotransmitter acetylcholine (ACh) at cholinergic synapses, as well as at neuromuscular junctions (Soreq and Seidman, 2001). In addition to its catalytic function of the hydrolysis of acetylcholine, AChE has been shown to be involved in many non-cholinergic functions, such as cell growth, stem cell differentiation (Sperling et al., 2008; Falugi and Aluigi, 2012), neuritogenesis, cell adhesion (Paraoanu and Layer, 2008), synaptogenesis, activation of dopaminergic neurons, tumorigenesis, amyloid fibril assembly (Inestrosa et al., 1996; Alvarez et al., 1997), haematopoiesis and thrombopoiesis (Greenfield, 1996; Layer, 1996; Small et al., 1996). The role of acetylcholinesterase in modulating the regulation of cholinergic function is still being investigated (Shaked et al., 2009; Schliebs and Arendt, 2011). The role of AChE inhibitors in many neurodegenerative and neurodevelopmental pathologies is also being studied (Hargreaves, 2012; Li et al., 2012).

Homology

AChE is widely conserved in the animal kingdom and is found in mammals, Drosophila, C. elegans and Torpedo californica, among others.

Mutations

Note

No natural disease-causing mutations have been reported but a number of single nucleotide polymorphisms (SNPs) are known which may affect transcriptional activity and immune properties.

Implicated in

Entity name
Primary ovarian carcinomas
Note
Significant amplification and mutagenesis of both the ache and the highly homologous BChE gene were identified in malignant tumors. The frequent co-amplification in ovarian carcinomas of ACHE implicates cholinesterases in neoplastic growth and/or proliferation (Zakut et al., 1990).
Entity name
Glioblastoma multiforme
Note
AChE mRNA accumulates in primary human astrocytomas in a manner associated with these tumors grade of aggressiveness (Perry et al., 2002). CREB regulation allows AChE-R-induced, PKA-mediated proliferation of glioblastoma tumors (Perry et al., 2004).
Entity name
Leukemia
Note
AChE-S may be a regulator of hematopoiesis, affecting cell fate decisions downstream to the GEMM progenitor cells (Perry et al., 2007). Deletion of the acetylcholinesterase locus at 7q22 is associated with myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) (Stephenson et al., 1996).
Entity name
Breast cancer
Note
In a recent study, amplifications and deletions in the AChE and BChE genes were investigated in sporadic breast tumors using real-time polymerase chain reaction and the relative quantification method and the majority of the tumor tissues showed a notable number of both deletions and amplifications of both the AChE and BChE genes (Bernardi et al., 2010).
Entity name
Alzheimers disease
Note
The loss of cholinergic neurons has long been believed to be an important aspect of Alzheimers pathology (Oddo and LaFerla, 2006; Schliebs and Arendt, 2011) and increasing the level of acetylcholine by the use of cholinesterase inhibitors is one of the few pharmacological interventions available for the treatment of Alzheimers disease (Birks, 2006; Shanks et al., 2009). AChE has been identified in the amyloid plaques found in Alzheimers disease and the isoforms of AChE have different effects on the extent of plaque development (Berson et al., 2008).
Entity name
Inflammation
Note
Being a major regulator of acetylcholine levels, AChE may relieve the cholinergic blockade of inflammation (Shaked et al., 2009). Correspondingly, increasing levels of the AChE-targeted microRNA-132, and presumably other AChE-targeted microRNAs can potentiate this blockade (Hanin and Soreq, 2011).

Bibliography

Pubmed IDLast YearTitleAuthors
93250951997Acetylcholinesterase promotes the aggregation of amyloid-beta-peptide fragments by forming a complex with the growing fibrils.Alvarez A et al
201938492010Amplification and deletion of the ACHE and BCHE cholinesterase genes in sporadic breast cancer.Bernardi CC et al
180561602008Changes in readthrough acetylcholinesterase expression modulate amyloid-beta pathology.Berson A et al
164375322006Cholinesterase inhibitors for Alzheimer's disease.Birks J et al
225297772012Early appearance and possible functions of non-neuromuscular cholinesterase activities.Falugi C et al
87923281996Non-classical actions of cholinesterases: role in cellular differentiation, tumorigenesis and Alzheimer's disease.Greenfield S et al
220071582011Cholinesterase-Targeting microRNAs Identified in silico Affect Specific Biological Processes.Hanin G et al
224112442012Neurodegenerations induced by organophosphorous compounds.Hargreaves AJ et al
86080061996Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer's fibrils: possible role of the peripheral site of the enzyme.Inestrosa NC et al
87923291996Non-classical actions of cholinesterases: role in cellular differentiation, tumorigenesis and Alzheimer's disease.Layer PG et al
224011782012Evaluation of epidemiology and animal data for risk assessment: chlorpyrifos developmental neurobehavioral outcomes.Li AA et al
82485011993Structure and functions of acetylcholinesterase and butyrylcholinesterase.Massoulié J et al
165163102006Virtues and woes of AChE alternative splicing in stress-related neuropathologies.Meshorer E et al
164488082006The role of nicotinic acetylcholine receptors in Alzheimer's disease.Oddo S et al
182058322008Acetylcholinesterase in cell adhesion, neurite growth and network formation.Paraoanu LE et al
174762782007Acetylcholinesterase/C terminal binding protein interactions modify Ikaros functions, causing T lymphopenia.Perry C et al
151533402004CREB regulates AChE-R-induced proliferation of human glioblastoma cells.Perry C et al
211459182011The cholinergic system in aging and neuronal degeneration.Schliebs R et al
200051352009MicroRNA-132 potentiates cholinergic anti-inflammatory signaling by targeting acetylcholinesterase.Shaked I et al
196787542009Cholinesterase inhibition: is there evidence for disease-modifying effects?Shanks M et al
185860192008Acetylcholinesterase: how is structure related to function?Silman I et al
87923271996Non-classical actions of cholinesterases: role in cellular differentiation, tumorigenesis and Alzheimer's disease.Small DH et al
112837522001Acetylcholinesterase--new roles for an old actor.Soreq H et al
185888652008Characterisation of cholinesterase expression during murine embryonic stem cell differentiation.Sperling LE et al
86372181996Deletion of the acetylcholinesterase locus at 7q22 associated with myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML).Stephenson J et al
83439761993Structure and regulation of expression of the acetylcholinesterase gene.Taylor P et al
23948391990Acetylcholinesterase and butyrylcholinesterase genes coamplify in primary ovarian carcinomas.Zakut H et al

Other Information

Locus ID:

NCBI: 43
MIM: 100740
HGNC: 108
Ensembl: ENSG00000087085

Variants:

dbSNP: 43
ClinVar: 43
TCGA: ENSG00000087085
COSMIC: ACHE

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000087085ENST00000241069P22303
ENSG00000087085ENST00000302913P22303
ENSG00000087085ENST00000411582P22303
ENSG00000087085ENST00000412389P22303
ENSG00000087085ENST00000419336P22303
ENSG00000087085ENST00000426415C9J2S3
ENSG00000087085ENST00000428317P22303
ENSG00000087085ENST00000430554C9JZL6
ENSG00000087085ENST00000440755F8WAR7
ENSG00000087085ENST00000441605C9JD78
ENSG00000087085ENST00000442452F8WD34
ENSG00000087085ENST00000445236A0A498U6H7
ENSG00000087085ENST00000454485F8WD68

Expression (GTEx)

0
10
20
30
40
50
60
70
80

Pathways

PathwaySourceExternal ID
Glycerophospholipid metabolismKEGGko00564
Glycerophospholipid metabolismKEGGhsa00564
Cholinergic synapseKEGGhsa04725
Metabolism of proteinsREACTOMER-HSA-392499
Peptide hormone metabolismREACTOMER-HSA-2980736
Synthesis, secretion, and deacylation of GhrelinREACTOMER-HSA-422085
Neuronal SystemREACTOMER-HSA-112316
Transmission across Chemical SynapsesREACTOMER-HSA-112315
Neurotransmitter Clearance In The Synaptic CleftREACTOMER-HSA-112311
MetabolismREACTOMER-HSA-1430728
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Phospholipid metabolismREACTOMER-HSA-1483257
Glycerophospholipid biosynthesisREACTOMER-HSA-1483206
Synthesis of PCREACTOMER-HSA-1483191

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA443319Alzheimer DiseaseDiseaseClinicalAnnotationassociatedPD18780301
PA451262rivastigmineChemicalClinicalAnnotationassociatedPD18780301

References

Pubmed IDYearTitleCitations
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
162134672005Butyrylcholinesterase, paraoxonase, and albumin esterase, but not carboxylesterase, are present in human plasma.84
201380302010Acetylcholinesterase: from 3D structure to function.63
197306832009The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.59
191561682009Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis.46
165163102006Virtues and woes of AChE alternative splicing in stress-related neuropathologies.41
151237272004Combinatorial complexity of 5' alternative acetylcholinesterase transcripts and protein products.35
190860532009Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment.34
203989082010Comprehensive copy number variant (CNV) analysis of neuronal pathways genes in psychiatric disorders identifies rare variants within patients.32
150602812004Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in Health, Risk Factors, Exercise Training, and Genetics study.30

Citation

Hermona Soreq ; David S Greenberg

ACHE (acetylcholinesterase)

Atlas Genet Cytogenet Oncol Haematol. 2012-05-01

Online version: http://atlasgeneticsoncology.org/gene/44317/ache