Making connections: cholinesterase-domain proteins in the CNS

Scholl, Francisco G.; Scheiffele, Peter

doi:10.1016/j.tins.2003.09.004

Cited by 65 publications

(46 citation statements)

References 57 publications

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“…5 In this reporter, the cis-HCV protease inactivates the Venus FP, producing a non-fluorescent protein. Fluorescent protein can be obtained by adding the specific HCV protease inhibitor, BILN-2061 (28).…”

Section: Methodsmentioning

confidence: 99%

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Neuroligin Trafficking Deficiencies Arising from Mutations in the α/β-Hydrolase Fold Protein Family

Jaco

Lin

Dubi

et al. 2010

Journal of Biological Chemistry

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Despite great functional diversity, characterization of the ␣/␤-hydrolase fold proteins that encompass a superfamily of hydrolases, heterophilic adhesion proteins, and chaperone domains reveals a common structural motif. By incorporating the R451C mutation found in neuroligin (NLGN) and associated with autism and the thyroglobulin G2320R (G221R in NLGN) mutation responsible for congenital hypothyroidism into NLGN3, we show that mutations in the ␣/␤-hydrolase fold domain influence folding and biosynthetic processing of neuroligin3 as determined by in vitro susceptibility to proteases, glycosylation processing, turnover, and processing rates. We also show altered interactions of the mutant proteins with chaperones in the endoplasmic reticulum and arrest of transport along the secretory pathway with diversion to the proteasome. Time-controlled expression of a fluorescently tagged neuroligin in hippocampal neurons shows that these mutations compromise neuronal trafficking of the protein, with the R451C mutation reducing and the G221R mutation virtually abolishing the export of NLGN3 from the soma to the dendritic spines. Although the R451C mutation causes a local folding defect, the G221R mutation appears responsible for more global misfolding of the protein, reflecting their sequence positions in the structure of the protein. Our results suggest that disease-related mutations in the ␣/␤-hydrolase fold domain share common trafficking deficiencies yet lead to discrete congenital disorders of differing severity in the endocrine and nervous systems.The neuroligins (NLGNs) 3 are postsynaptic proteins that associate with cognate presynaptic partners, the neurexins (1-3, ␣ and ␤) (NRXNs) (1, 2), and are essential for selectivity in synaptic function (3). By virtue of a common structure in their extracellular domain, the NLGNs fall in the ␣/␤-hydrolase fold superfamily of proteins. To date, proteins of this family are known to serve three general functions: 1) catalyzing the hydrolysis of ester and amide substrates as with acetylcholinesterase, 2) serving as chaperones for secretion of hormone precursors such as with thyroglobulin (Tg), and 3) mediating heterophilic synaptic adhesion interactions as found for neuroligin. The common structure of the ␣/␤-hydrolase fold domain shared by the family members (4) suggests that despite the different functions, these proteins share common mechanisms of protein folding and processing.In NLGN, the ␣/␤-hydrolase fold domain is crucial for transsynaptic interactions with NRXN. Both the NRXNs and the NLGNs are transmembrane proteins; they facilitate associations with intracellular proteins at synaptic loci in pre-and postsynaptic neurons (5). Genetic aberrations in both the NLGN and the NRXN protein families have been identified in patients with autism spectrum disorders (6 -13). The R451C substitution in the ␣/␤-hydrolase fold domain of NLGN3 was found in two autistic brothers (7), and this mutation has been characterized extensively. Protein derived from R451C NLGN3 cDNA is predomin...

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Section: Methodsmentioning

confidence: 99%

“…Both the NRXNs and the NLGNs are transmembrane proteins; they facilitate associations with intracellular proteins at synaptic loci in pre-and postsynaptic neurons (5). Genetic aberrations in both the NLGN and the NRXN protein families have been identified in patients with autism spectrum disorders (6 -13).…”

mentioning

confidence: 99%

Neuroligin Trafficking Deficiencies Arising from Mutations in the α/β-Hydrolase Fold Protein Family

Jaco

Lin

Dubi

et al. 2010

Journal of Biological Chemistry

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“…0.05), suggesting that it had undergone massive redistribution. The AChE-like synaptic protein neuroligin 1 [31,32] is involved in synaptic adhesion, inter-neuronal signaling and site-specific recruitment of synaptic proteins during synaptogenesis [33] .…”

Section: Bw Treatment Affects Synaptic Nmda Receptor Functions and Cementioning

confidence: 99%

Peripheral Site Acetylcholinesterase Blockade Induces RACK1-Associated Neuronal Remodeling

Farchi

Ofek²,

Podoly³

et al. 2007

Neurodegener Dis

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Background: Peripheral anionic site (PAS) blockade of acetylcholinesterase (AChE) notably affects neuronal activity and cyto-architecture, however, the mechanism(s) involved are incompletely understood. Objective: We wished to specify the PAS extracellular effects on specific AChE mRNA splice variants, delineate the consequent cellular remodeling events, and explore the inhibitory effects on interchanging RACK1 interactions. Methods: We exposed rat hippocampal cultured neurons to BW284C51, the peripheral anionic site inhibitor of AChE, and to the non-selective AChE active site inhibitor, physostigmine for studying the neuronal remodeling of AChE mRNA expression and trafficking. Results: BW284C51 induced overexpression of both AChE splice variants, yet promoted neuritic translocation of the normally rare AChE-R, and retraction of AChE-S mRNA in an antisense-suppressible manner. BW284C51 further caused modest decreases in the expression of the scaffold protein RACK1 (receptor for activated protein kinase βII), followed by drastic neurite retraction of both RACK1 and the AChE homologue neuroligin1, but not the tubulin-associated MAP2 protein. Accompanying BW284C51 effects involved decreases in the Fyn kinase and membrane insertion of the glutamate receptor NR2B variant and impaired glutamatergic activities of treated cells. Intriguingly, molecular modeling suggested that direct, non-catalytic competition with Fyn binding by the RACK1-interacting AChE-R variant may be involved. Conclusions: Our findings highlight complex neuronal AChE-R/RACK1 interactions and are compatible with the hypothesis that peripheral site AChE inhibitors induce RACK1-mediated neuronal remodeling, promoting suppressed glutamatergic neurotransmission.

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“…(33) The strong sequence similarities of ChEs with adhesion proteins such as neurotactin and neuroligin suggests that they are members of a family of adhesion proteins that is present in fungi and multicellular animals. (9,34) It was shown in in vitro experiments that AChE has adhesive properties; it can replace the extracellular domain of neurotactin for heterophillic interaction in vitro, (35) and it is able to promote fibrillar formation of beta amyloid. (20) In mice overexpressing AChE, neurexin-Ibeta, the heterophilic ligand of the AChE-related neuronal cell surface protein neuroligin, was drastically lower in embryonic transgenic spl cord than in controls.…”

Section: Introductionmentioning

confidence: 99%

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

Cousin¹,

Strähle

Chatonnet³

2005

Bioessays

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Acetylcholinesterase (AChE) hydrolyses acetylcholine (ACh) ensuring the fast clearance of released neurotransmitter at cholinergic synapses. Many studies led to the hypothesis that AChE and the closely related enzyme butyrylcholinesterase (BChE) may play other, non-hydrolytic roles during development. In this review, we compare data from in vivo studies performed on invertebrate and vertebrate genetic models. The loss of function of ache in these systems is responsible for the appearance of several phenotypes. In all aspects so far studied, the phenotypes can be explained by an excess of the undegraded substrate, ACh, leading to misfunction and pathological alterations. Thus, the lack of AChE catalytic activity in the mutants appears to be solely responsible for the observed phenotypes. None of them appears to require the postulated adhesive or other non-hydrolytic functions of AChE.

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Making connections: cholinesterase-domain proteins in the CNS

Cited by 65 publications

References 57 publications

Neuroligin Trafficking Deficiencies Arising from Mutations in the α/β-Hydrolase Fold Protein Family

Neuroligin Trafficking Deficiencies Arising from Mutations in the α/β-Hydrolase Fold Protein Family

Peripheral Site Acetylcholinesterase Blockade Induces RACK1-Associated Neuronal Remodeling

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

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