Functional redundancy of acetylcholinesterase and neuroligin in mammalian neuritogenesis

Grifman, Mirta; Galyam, N.; Seidman, Shlomo; Soreq, Hermona

doi:10.1073/pnas.95.23.13935

Cited by 112 publications

(83 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…13 However, the 534 residue core domain that is common to the two AChE variants shares sequence and function homologies with neuroligin, a postsynaptic cell adhesion molecule of excitatory synapses, 31,32 which triggers presynaptic development in contacting axons. 33 It is tempting to speculate that, under stress, excess AChE-R may compete with neuroligin, potentially impairing its interaction with b-neuroexin and modifying the subsequent activation of PSD95.…”

Section: Discussionmentioning

confidence: 99%

Stress-induced alternative splicing of acetylcholinesterase results in enhanced fear memory and long-term potentiation

et al. 2003

View full text Add to dashboard Cite

Stress insults intensify fear memory; however, the mechanism(s) facilitating this physiological response is still unclear. Here, we report the molecular, neurophysiological and behavioral findings attributing much of this effect to alternative splicing of the acetylcholinesterase (AChE) gene in hippocampal neurons. As a case study, we explored immobilization-stressed mice with intensified fear memory and enhanced long-term potentiation (LTP), in which alternative splicing was found to induce overproduction of neuronal 'readthrough' AChE-R (AChE-R). Selective downregulation of AChE-R mRNA and protein by antisense oligonucleotides abolished the stress-associated increase in AChE-R, the elevation of contextual fear and LTP in the hippocampal CA1 region. Reciprocally, we intrahippocampally injected a synthetic peptide representing the C-terminal sequence unique to AChE-R. The injected peptide, which has been earlier found to exhibit no enzymatic activity, was incorporated into cortical, hippocampal and basal nuclei neurons by endocytosis and retrograde transport and enhanced contextual fear. Compatible with this hypothesis, inherited AChE-R overexpression in transgenic mice resulted in perikaryal clusters enriched with PKCbII, accompanied by PKCaugmented LTP enhancement. Our findings demonstrate a primary role for stress-induced alternative splicing of the AChE gene to elevated contextual fear and synaptic plasticity, and attribute to the AChE-R splice variant a major role in this process.

show abstract

Section: Discussionmentioning

confidence: 99%

Stress-induced alternative splicing of acetylcholinesterase results in enhanced fear memory and long-term potentiation

et al. 2003

View full text Add to dashboard Cite

show abstract

“…AChE is predominantly expressed in cholinergic tissues (muscle and neurons); however, it is also expressed in some noncholinergic neurons and nonexcitable cells, such as hematopoietic cells (Hammond et al, 1994;Bernard et al, 1995;Brimijoin and Hammond, 1996;Lev-Lehman et al, 1997;Chan et al, 1998). As a result, several noncholinergic roles have been described for AChE including in neurite elongation, cell adhesion, and synaptogenesis (Brimijoin and Hammond, 1996;Koenigsberger et al, 1997;Grifman et al, 1998;Sternfeld et al, 1998;Lev-Lehman et al, 2000;Sharma et al, 2001) (for review, see Soreq and Seidman, 2001). In addition to having these nonclassical roles, AChE and its different molecular forms have been implicated in the development of neuronal tumors, in Alzheimer's disease, and in post-traumatic stress disorder (Karpel et al, 1994;Kaufer et al, 1998;Perry et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

The RNA-Binding Protein HuD Binds Acetylcholinesterase mRNA in Neurons and Regulates its Expression after Axotomy

Deschênes‐Furry¹,

Mousavi²,

Bolognani³

et al. 2007

J. Neurosci.

View full text Add to dashboard Cite

After axotomy, expression of acetylcholinesterase (AChE) is greatly reduced in the superior cervical ganglion (SCG); however, the molecular events involved in this response remain unknown. Here, we first examined AChE mRNA levels in the brain of transgenic mice that overexpress human HuD. Both in situ hybridization and reverse transcription-PCR demonstrated that AChE transcript levels were increased by more than twofold in the hippocampus of HuD transgenic mice. Additionally, direct interaction between the HuD transgene product and AChE mRNA was observed. Next, we examined the role of HuD in regulating AChE expression in intact and axotomized rat SCG neurons. After axotomy of the adult rat SCG neurons, AChE transcript levels decreased by 50 and 85% by the first and fourth day, respectively. In vitro mRNA decay assays indicated that the decrease in AChE mRNA levels resulted from changes in the stability of presynthesized transcripts. A combination of approaches performed using the region that directly encompasses an adenylate and uridylate (AU)-rich element within the AChE 3Ј-untranslated region demonstrated a decrease in RNA-protein complexes in response to axotomy of the SCG and, specifically, a decrease in HuD binding. After axotomy, HuD transcript and protein levels also decreased. Using a herpes simplex virus construct containing the human HuD sequence to infect SCG neurons in vivo, we found that AChE and GAP-43 mRNA levels were maintained in the SCG after axotomy. Together, the results of this study demonstrate that AChE expression in neurons of the rat SCG is regulated via post-transcriptional mechanisms that involve the AU-rich element and HuD.

show abstract

“…In addition to this active site, cholinesterases bind a second substrate molecule through a so-called peripheral anionic site (PAS), which is lined with charged amino acid residues (15). Although NLs and ChE share substantial sequence similarity and show apparently redundant function in some assays (16), swapping the ChE-domain of NL1 with that of AChE abolishes NRX binding of NL1 and results in a protein with dominant-negative function in cultured neurons (17,18). Despite these differences, the analogy between NLs and ChE has enabled preliminary structural modeling based on sequence alignments (10).…”

mentioning

confidence: 99%

Crystal structure of the extracellular cholinesterase-like domain from neuroligin-2

Koehnke

Jin

Budreck

et al. 2008

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

View full text Add to dashboard Cite

Neuroligins (NLs) are catalytically inactive members of a family of cholinesterase-like transmembrane proteins that mediate cell adhesion at neuronal synapses. Postsynaptic neuroligins engage in Ca 2؉ -dependent transsynaptic interactions via their extracellular cholinesterase domain with presynaptic neurexins (NRXs). These interactions may be regulated by two short splice insertions (termed A and B) in the NL cholinesterase domain. Here, we present the 3.3-Å crystal structure of the ectodomain from NL2 containing splice insertion A (NL2A). The overall structure of NL2A resembles that of cholinesterases, but several structural features are unique to the NL proteins. First, structural elements surrounding the esterase active-site region differ significantly between active esterases and NL2A. On the opposite surface of the NL2A molecule, the positions of the A and B splice insertions identify a candidate NRX interaction site of the NL protein. Finally, sequence comparisons of NL isoforms allow for mapping the location of residues of previously identified mutations in NL3 and NL4 found in patients with autism spectrum disorders. Overall, the NL2 structure promises to provide a valuable model for dissecting NL isoform-and synapse-specific functions.acetylcholinesterase-like ͉ neurexin

show abstract

Functional redundancy of acetylcholinesterase and neuroligin in mammalian neuritogenesis

Abstract: Accumulated evidence attributes noncatalytic morphogenic activitie(s) to acetylcholinesterase (AChE

Cited by 112 publications

References 29 publications

Stress-induced alternative splicing of acetylcholinesterase results in enhanced fear memory and long-term potentiation

Stress-induced alternative splicing of acetylcholinesterase results in enhanced fear memory and long-term potentiation

The RNA-Binding Protein HuD Binds Acetylcholinesterase mRNA in Neurons and Regulates its Expression after Axotomy

Crystal structure of the extracellular cholinesterase-like domain from neuroligin-2

Contact Info

Product

Resources

About