title: ARP, the cleavable C-terminal peptide of "readthrough" acetylcholinesterase, promotes neuronal development and plasticity.
abstract: The mammalian acetylcholinesterase (ACHE) gene gives rise to diverse enzymatically active proteins with three different carboxyl termini. In the brain, the normally rare readthrough AChE-R monomer accumulates under embryonic development and in adults following psychological stress, head injury, or exposure to AChEs. In the prenatal developing cortex, its unique C-terminal peptide ARP associates with radial glial fibers supporting neuronal migration. In contrast, the major synaptic AChE-S variant appears in the migrating neurons themselves. Moreover, antisense suppression of AChE-R attenuates neuronal migration, allowing increased proliferation of neuronal progenitors. In the adult brain, neuronal AChE-R is either secreted or accumulates intraneuronally, where it interacts through ARP with the scaffold protein RACK1 and activated PKC-betaII. This associates with increased PKC-betaII activity, which shuttles to submembranal clusters (e.g., in hyperactivated hippocampal neurons). Cleavage yields the AChE-R-specific C-terminal peptide, including immunopositive ARP. Importantly, intrahippocampal injection of synthetic ARP was followed by its efficient neuronal penetration and retrograde transport into cortical and basal nuclei neurons. Moreover, ARP-injected mice presented increased stress-induced contextual fear, inhibitable by antisense suppression of AChE-R mRNA. Together, our findings point at the cleavable ARP peptide as a key regulator of neuronal development and plasticity and suggest its use as a drug target and/or research and therapeutic tool.
authors.affiliation: Department of Neurology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Amir
authors.initials: A
authors.lastname: Dori
authors.forename: Hermona
authors.initials: H
authors.lastname: Soreq
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D017398:Alternative Splicing; D000818:Animals; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D008568:Memory; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D012322:RNA Precursors / Q000378:metabolism; D000075370:Receptors for Activated C Kinase; D011950:Receptors, Cholinergic / Q000378:metabolism; D013315:Stress, Psychological
chemical_list: D010446:Peptide Fragments; D010455:Peptides; D020033:Protein Isoforms; D012322:RNA Precursors; D000075370:Receptors for Activated C Kinase; D011950:Receptors, Cholinergic; C070301:peptide I; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D000110:Acetylcholinesterase; D000109:Acetylcholine