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    • PD 0332991 synthesis br AChE variants and their functions

    2022-11-30


    AChE variants and their functions The AChE gene generates several splice variants of AChE which are designated as hydrophobic (H), readthrough (R) and tailed (T) forms differing in membrane association and also localisation on a tissue and sub-cellular level. They all undergo significant posttranslational modifications providing a wide platform for protein-protein and cellular interactions [51]. The individual subunits of AChE can associate with each other, forming both dimers and tetramers and in the brain, tetramers of AChET form the functional units at cholinergic synapses [52]. In neuronal PD 0332991 synthesis AChET is bound to the membrane by the Proline Rich Membrane Anchor (PRiMA), a 20 kDa protein [53], [54]. PRiMA has a Proline Rich Attachment Domain (PRAD), like its counterpart ColQ, which serves as a membrane anchor for AChE at neuromuscular junctions [55], [56]. The AChE-PRiMA association occurs between the C-terminal t peptides of AChE and the PRAD of PRiMA. It has also been suggested that disulphide bonds form between four Cys residues at the N-terminus of PRiMA and the C-terminal Cys in the AChET peptide [53]. Immunofluorescence studies have shown strong co-localisation between AChE and PRiMA in cholinergic neurons but not in dopaminergic nor GABAergic neurons [57]. Expression of transcripts encoding both the synaptic AChE-T isoform and its membrane anchoring peptide PRiMA-I has also been reported in fibroblasts where AChE appeared to be functionally important for polarised cell migration [58]. Moreover, there was precise co-localisation of AChE with APP and the extracellular matrix protein perlecan [58], which suggests that the cell surface AChE in a novel signalling complex with these two proteins might be involved in the mechanisms of migration in adherent cells. Among AChE splice variants, its readthrough form (AChE-R) is of particular interest since its up-regulation has been shown in various stress-models [59]. Moreover, stress-induced alternative splicing of the AChE gene resulting in AChE-R production was linked to elevated contextual fear and synaptic plasticity [60] suggesting that AChE-R can act as a stress signal molecule [61]. AChE-R, together with its cleavable 26 amino-acid C-terminal peptide named ARP, also has a potential protective role which has been shown in various paradigms including exposure to chemical warfare agents, bacterial lipopolysaccharides or Aβ [61], [62], [63]. Together with mitochondrial activity, AChE-R was suggested to play a role in cholinergic adaptation to low doses of Aβ [64]. Despite its difference in substrate specificity and functions, BChE has similar structural properties to AChE in regard of oligomerisation and membrane anchorage via PRiMA and ColQ [65], [66], [67]. Moreover, existence of natural PRiMA-linked AChE-BChE hybrids were reported in chicken brain with their levels being increased during development, suggesting that they might play a role in maturation of the cholinergic system [68]. In AD brain BChE, like AChE, was found in association with amyloid deposits [69] and BChE was shown to PD 0332991 synthesis attenuate amyloid fibril formation both in humans and animal models [7], [70], [71]. BChE levels were shown to increase with AD development which makes it, together with AChE, a potential therapeutic target [72], [73]. Knocking-down BChE in an AD mice model resulted in reduced amyloid formation suggesting an important role of this enzyme for amyloid accumulation [74]. Involvement of both AChE and BChE in a “cholinergic anti-inflammatory pathway” and their increased activity in plasma and tissue in various clinical conditions also suggests them as markers of low-grade systemic inflammation [75]. Currently, highly selective BuChE inhibitors are suggested to have potential therapeutic benefits in the treatment of diabetes mellitus, AD and other related dementias [76].
    APP isoforms and their functional roles Alternative splicing of mammalian APP mRNA generates three major isoforms: APP695 APP751, and APP770. All three protein products have a rather similar structure with a short transmembrane domain, a large extracellular domain region and multiple binding domains and have numerous, albeit distinctive functions, both in the brain and in the periphery (for review see Refs. [1], [77]). APP695 is mostly expressed in neurones while the two other isoforms are more abundant in glia and astrocytes [78]. Proteolytic processing of APP isoforms generates a variety of proteolytic fragments, which have different compartmentalisation due to their topographic specificity both on the cell surface and inside the cell [79], [80]. In neuronal cells APP695 was found to be processed mostly by the β-secretase pathway generating transcriptionally active AICD [81]. Overexpression of various APP isoforms in cells were shown to result in a different pattern of expression of several Aβ-clearing proteins, including transthyretin and insulin-degrading enzyme [82], [83].