Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology

ArticleinNature Reviews Neuroscience 13(6):395-406 · May 2012with37 Reads
Impact Factor: 31.43 · DOI: 10.1038/nrn3228 · Source: PubMed
Abstract

Caspases are cysteine proteases that mediate apoptosis, which is a form of regulated cell death that effectively and efficiently removes extra and unnecessary cells during development. In the mature nervous system, caspases are not only involved in mediating cell death but also regulatory events that are important for neural functions, such as axon pruning and synapse elimination, which are necessary to refine mature neuronal circuits. Furthermore, caspases can be reactivated to cause cell death as well as non-lethal changes in neurons during numerous pathological processes. Thus, although a global activation of caspases leads to apoptosis, restricted and localized activation may control normal physiology and pathophysiology in living neurons. This Review explores the multiple roles of caspase activity in neurons.

    • "Caspases are considered essential apoptotic regulators of both apoptotic pathways and they are found in latent form in different subcellular compartments, being activated by distinct mechanisms such as proteolysis, oligomerisation or binding to membrane receptors or regulating factors (Hyman & Yuan, 2012; Ramuz et al., 2003). Specific subcellular localisation of caspases implies distinct roles during development according to the cell type. "
    [Show abstract] [Hide abstract] ABSTRACT: Salivary gland (SG) development is based on branching morphogenesis, in which programmed cell death has been proposed to play a role in cell signalling and organ shaping. In the mouse salivary gland apoptosis has been suggested to play a key role in lumen formation, removing the central cells of the epithelial stalks. Here we analyse the expression of several anti- and pro-regulators of apoptosis during human SG development in a range of developmental stages.
    Full-text · Article · May 2016
    • "While this seems counter-intuitive, in recent years downstream caspases have been implicated in a number of " non-apoptotic " processes [78] . Some, such as terminal differentiation, enucleation or dendritic pruning [79,80], share morphological features with apoptotic cell death, so could be considered " curtailed " versions of apoptosis [81]. However, activated downstream caspases have also been detected within proliferating T cells [82,83] , so such proteolytic activity is evidently compatible with clonogenic survival in some circumstances. "
    [Show abstract] [Hide abstract] ABSTRACT: When chemotherapy and radiotherapy are effective, they function by inducing DNA damage in cancerous cells, which respond by undergoing apoptosis. Some adverse effects can result from collateral destruction of non-cancerous cells, via the same mechanism. Therapy-related cancers, a particularly serious adverse effect of anti-cancer treatments, develop due to oncogenic mutations created in non-cancerous cells by the DNA damaging therapies used to eliminate the original cancer. Physiologically achievable concentrations of direct apoptosis inducing anti-cancer drugs that target Bcl-2 and IAP proteins possess negligible mutagenic activity, however death receptor agonists like TRAIL/Apo2L can provoke mutations in surviving cells, probably via caspase-mediated activation of the nuclease CAD. In this study we compared the types of mutations sustained in the HPRT and TK1 loci of clonogenically competent cells following treatment with TRAIL or the alkylating agent ethyl methanesulfonate (EMS). As expected, the loss-of-function mutations in the HPRT or TK1 loci triggered by exposure to EMS were almost all transitions. In contrast, only a minority of the mutations identified in TRAIL-treated clones lacking HPRT or TK1 activity were substitutions. Almost three quarters of the TRAIL-induced mutations were partial or complete deletions of the HPRT or TK1 genes, consistent with sub-lethal TRAIL treatment provoking double strand breaks, which may be mis-repaired by non-homologous end joining (NHEJ). Mis-repair of double-strand breaks following exposure to chemotherapy drugs has been implicated in the pathogenesis of therapy-related cancers. These data suggest that TRAIL too may provoke oncogenic damage to the genomes of surviving cells.
    Full-text · Article · Feb 2016
    • "Although the cell death pathway involved in Aβ cytotoxicity has not been clearly elucidated, studies have implicated apoptosis because apoptosis-related proteins such as caspases are activated when cells are treated with Aβ peptides [8,9]. Caspase, a hallmark enzyme of apoptosis, is synthesized as a zymogen, which is activated by apoptotic signals [10] . Of the 2 well-defined apoptotic pathways, receptormediated apoptosis or extrinsic apoptosis is characterized by the formation of death-inducing signaling complex (DISC) [11] . "
    [Show abstract] [Hide abstract] ABSTRACT: β-Amyloid (Aβ), a hallmark peptide of Alzheimer's disease, induces both caspase-dependent apoptosis and non-apoptotic cell death. In this study, we examined caspase-independent non-apoptotic cell death preceding caspase activation in Aβ42-treated cells. We first determined the optimal treatment conditions for inducing cell death without caspase activation and selected a double-treatment method involving the incubation of cells with Aβ42 for 4 and 6 h (4 + 6 h sample). We observed that levels of lamin A (LA) and lamin B (LB) were reduced in the 4 + 6 h samples. This reduction was decreased by treatment with suc-AAPF-CMK, an inhibitor of nuclear scaffold (NS) protease, but not by treatment with z-VAD-FMK, a pan-caspase inhibitor. In addition, suc-AAPF-CMK decreased the changes in nuclear morphology observed in cells in the 4 + 6 h samples, which were different from nuclear fragmentation observed in STS-treated cells. Furthermore, suc-AAPF-CMK inhibited cell death in the 4 + 6 h samples. LA and LB fragmentation occurred in the isolated nuclei and was also inhibited by suc-AAPF-CMK. Together, these data indicated that the fragmentation of LA and LB in the Aβ42-treated cells was induced by an NS protease, whose identity is not clearly determined yet. A correlation between Aβ42 toxicity and the lamin fragmentation by NS protease suggests that inhibition of the protease could be an effective method for controlling the pathological process of AD.
    Full-text · Article · Feb 2016 · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
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