Neuronal death signaling pathways triggered by mutant LRRK2

2017 ◽  
Vol 45 (1) ◽  
pp. 123-129 ◽  
Author(s):  
Hardy J. Rideout
Keyword(s):  
Cell Death ◽  
Neuronal Death ◽  
Specific Cell ◽  
Clear Understanding ◽  
Gene Encoding ◽  
In Vivo Models ◽  
Cellular Models ◽  
Inhibitory Function ◽  
Mutant Lrrk2

Autosomal dominantly inherited mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. While considerable progress has been made in understanding its function and the many different cellular activities in which it participates, a clear understanding of the mechanism(s) of the induction of neuronal death by mutant forms of LRRK2 remains elusive. Although several in vivo models have documented the progressive loss of dopaminergic neurons of the substantia nigra, more complete interrogations of the modality of neuronal death have been gained from cellular models. Overexpression of mutant LRRK2 in neuronal-like cell lines or in primary neurons induces an apoptotic type of cell death involving components of the extrinsic as well as intrinsic death pathways. While informative, these studies are limited by their reliance upon isolated neuronal cells; and the pathways triggered by mutant LRRK2 in neurons may be further refined or modulated by extracellular signals. Nevertheless, the identification of specific cell death-associated signaling events set in motion by the dominant action of mutant LRRK2, the loss of an inhibitory function of wild-type LRRK2, or a combination of the two, expands the landscape of potential therapeutic targets for future intervention in the clinic.

scholarly journals Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 376
Author(s):  
Chantal B. Lucini ◽  
Ralf J. Braun
Keyword(s):  
Cell Death ◽  
Oxygen Species ◽  
In Vivo Models ◽  
Dependent Cell ◽  
Cell Death Mechanisms ◽  
Sting Pathway ◽  
Mitochondrial Membrane Permeabilization

In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.

scholarly journals Apoptosis and in vivo models to study the molecules related to this phenomenon

2010 ◽  
Vol 8 (4) ◽  
pp. 495-497 ◽  
Author(s):  
Adriana Luchs ◽  
Claudia Pantaleão
Keyword(s):  
Cell Death ◽  
B Cell ◽  
Ectopic Expression ◽  
B Cell Lymphoma ◽  
Murine Models ◽  
In Vivo Models ◽  
Large B Cell Lymphoma ◽  
Pathological Conditions ◽  
Pharmacological Targets

ABSTRACT Apoptosis or programmed cell death is a physiological process, essential for eliminating cells in excess or that are no longer necessary to the organism, acting on tissue homeostasis, although the phenomenon is also involved in pathological conditions. Apoptosis promotes activation of biochemical pathways inside cells called caspase pathway, of the proteins responsible for the cleavage of several cell substrates, leading to cell death. Antiapoptotic members of the Bcl-2 family (B cell CLL/lymphoma 2), that belong to the intrinsic route of the activation of caspases, such as Bcl-xL (extra-large B-cell lymphoma) and Bcl-w (Bcl-2-like 2), act predominantly to prevent that pro-apoptotic members, such as Bax (Bcl-2-associated X protein) and Bak (Bcl-2 relative bak) lead to cell death. Antiapoptotic molecules are considered potentially oncogenic. Murine models are known to be valuable systems for the experimental analysis of oncogenes in vivo, and for the identification of pharmacological targets for cancer and to assess antitumor therapies. Given the importance of tumorigenesis studies on the immune responses to cancer and the possibility of investigating the participation of antiapoptotic molecules in tumor progression in vivo, the development of new models may be platforms for studies on tumorigenesis, immune antitumor responses, investigation of the ectopic expression of antiapoptotic molecules and immunotherapies for tumors.

Perforin-dependent apoptosis functionally compensates Fas deficiency in activation-induced cell death of human T lymphocytes

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4285-4292 ◽  
Author(s):  
Véronique Mateo ◽  
Michael Ménager ◽  
Geneviève de Saint-Basile ◽  
Marie-Claude Stolzenberg ◽  
Bertrand Roquelaure ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Lymphocytes ◽  
Peripheral Tolerance ◽  
Gene Encoding ◽  
Activation Induced Cell Death ◽  
Dependent Cell ◽  
Lymphoproliferative Syndrome ◽  
Dependent Pathway

Activation-induced cell death (AICD) is involved in peripheral tolerance by controlling the expansion of repeatedly stimulated T cells via an apoptotic Fas (CD95; APO-1)–dependent pathway. The TNFRSF-6 gene encoding Fas is mutated in children suffering from autoimmune lymphoproliferative syndrome (ALPS), which is characterized by lymphoproliferation and autoimmunity. We examined AICD in Fas-deficient T cells from ALPS patients. We showed that primary activated Fas-deficient T cells die by apoptosis after repeated T cell antigen receptor (TCR) stimulation despite resistance to Fas-mediated cell death. This Fas-independent AICD was found to be mediated through a cytotoxic granules-dependent pathway. Cytotoxic granules-mediated AICD was also detected in normal T lymphocytes though to a lesser extent. As expected, the cytotoxic granules-dependent AICD was abolished in T cells from Rab27a- or perforin-deficient patients who exhibited defective granules-dependent cytotoxicity. Supporting an in vivo relevance of the cytotoxic granules-dependent AICD in ALPS patients, we detected an increased number of circulating T lymphocytes expressing granzymes A and B. Altogether, these data indicated that the cytotoxic granules-dependent cell death in ALPS may compensate for Fas deficiency in T lymphocytes. Furthermore, they identified a novel AICD pathway as a unique alternative to Fas apoptosis in human peripheral T lymphocytes.

scholarly journals Iron toxicity, lipid peroxidation and ferroptosis after intracerebral haemorrhage

2019 ◽  
Vol 4 (2) ◽  
pp. 93-95 ◽  
Author(s):  
Jieru Wan ◽  
Honglei Ren ◽  
Jian Wang
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Intracerebral Haemorrhage ◽  
Neuronal Death ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Iron Toxicity ◽  
Secondary Brain Injury

Intracerebral haemorrhage (ICH) is a devastating type of stroke with high mortality and morbidity. However, we have few options for ICH therapy and limited knowledge about post-ICH neuronal death and related mechanisms. In the aftermath of ICH, iron overload within the perihaematomal region can induce lethal reactive oxygen species (ROS) production and lipid peroxidation, which contribute to secondary brain injury. Indeed, iron chelation therapy has shown efficacy in preclinical ICH studies. Recently, an iron-dependent form of non-apoptotic cell death known as ferroptosis was identified. It is characterised by an accumulation of iron-induced lipid ROS, which leads to intracellular oxidative stress. The ROS cause damage to nucleic acids, proteins and lipid membranes, and eventually cell death. Recently, we and others discovered that ferroptosis does occur after haemorrhagic stroke in vitro and in vivo and contributes to neuronal death. Inhibition of ferroptosis is beneficial in several in vivo and in vitro ICH conditions. This minireview summarises current research on iron toxicity, lipid peroxidation and ferroptosis in the pathomechanisms of ICH, the underlying molecular mechanisms of ferroptosis and the potential for combined therapeutic strategies. Understanding the role of ferroptosis after ICH will provide a vital foundation for cell death-based ICH treatment and prevention.

Role of glyoxalase-1 in trabectedin-resistant myxoid liposarcoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e23566-e23566
Author(s):  
Sonia Simonetti ◽  
Michele Iuliani ◽  
Francesco Pantano ◽  
Giulia Ribelli ◽  
Andrea Napolitano ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Viability ◽  
Cell Line ◽  
Myxoid Liposarcoma ◽  
Bioinformatics Analyses ◽  
In Vivo Models ◽  
Over Expression ◽  
Glyoxalase 1

e23566 Background: Glyoxalase-1 (Glo1) is involved in the detoxification of the endogenous reactive metabolite, methylglyoxal (MG), whose abnormal accumulation increases adduct levels and induce cell apoptosis. Previous studies demonstrated that increased Glo-1 expression was associated with cancer chemotherapy resistance. We performed bioinformatics analyses finding that Glo-1 mRNA over-expression was correlated with worse prognosis in patients affected by Soft Tissue Sarcoma (STS). On the bases of these evidences, we investigated the potential role of Glo1 expression as biomarker of tumor growth and drug resistance in STS. Methods: Trabectedin and MG cytoxicity was evaluated by MTT viability assay measured at spectrofluorometer. Apoptosis was analyzed by flow cytometry using Annexin V antibody and propidium iodide. Glo-1 expression analysis was performed by Western Blot using a mouse monoclonal anti-human Glo-1 antibody (NBP1-19015). Synergy analysis was calculated using Combenefit software and statistical analysis was performed by Student-t test using the program GraphPad-Prism. Results: As STS trabectedin resistant model, we used a myxoid-liposarcoma cell line (402-91 ET cells) that are not responsive to clinical doses of trabectedin contrary to the parental sensitive cell line (402-91 WT cells). Intriguingly, we found higher Glo-1 protein levels in 402-91 ET cells compared to 402-91 WT cells. The treatment of 402-91 ET cells with the specific Glo1 inhibitor S-p-bromobenzylglutathione cyclopentyl diester (BBGC), in combination with trabectedin (PharmaMar), significantly inhibited cell viability and increased apoptosis than trabectedin alone. In particular, the addition of BBGC reduced trabectedin EC50 (half-maximal effective concentration) from 20.4nM to 5.92nM in 402-91 ET cells, similar to that observed in 402-91 WT cells (4.92nM). To investigate if cell death was induced by MG accumulation following Glo1 inhibition, we evaluated 402-91 ET cell viability after treatment with different doses of MG in combination with trabectedin. The addition of MG restored sensitivity to trabectedin in 402-91 ET cells as well as BBGC. Conclusions: Our results highlight a new potential mechanism of trabectedin resistance mediated by Glo-1 over-expression. The use of the specific Glo-1 inhibitor, BBGC, restores trabectedin sensitivity in resistant cells leading to MG accumulation that, in turn, promotes cell death and apoptosis. These data provide a strong rationale to investigate Glo-1 inhibition strategy, in combination with trabectedin, in STS in vivo models.

scholarly journals Pancreatic Cancer–Specific Cell Death Induced In Vivo by Cytoplasmic-Delivered Polyinosine–Polycytidylic Acid

2014 ◽  
Vol 74 (21) ◽  
pp. 6224-6235 ◽  
Author(s):  
Praveen Bhoopathi ◽  
Bridget A. Quinn ◽  
Qin Gui ◽  
Xue-Ning Shen ◽  
Steven R. Grossman ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Specific Cell ◽  
Polycytidylic Acid

scholarly journals Irradiation-Induced Upregulation of miR-711 Inhibits DNA Repair and Promotes Neurodegeneration Pathways

2020 ◽  
Vol 21 (15) ◽  
pp. 5239 ◽  
Author(s):  
Boris Sabirzhanov ◽  
Oleg Makarevich ◽  
James P. Barrett ◽  
Isabel L. Jackson ◽  
Ethan P. Glaser ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Dna Repair ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Intrinsic Apoptosis ◽  
In Vivo Models ◽  
Neuroprotective Strategy ◽  
Radiation Induced

Radiotherapy for brain tumors induces neuronal DNA damage and may lead to neurodegeneration and cognitive deficits. We investigated the mechanisms of radiation-induced neuronal cell death and the role of miR-711 in the regulation of these pathways. We used in vitro and in vivo models of radiation-induced neuronal cell death. We showed that X-ray exposure in primary cortical neurons induced activation of p53-mediated mechanisms including intrinsic apoptotic pathways with sequential upregulation of BH3-only molecules, mitochondrial release of cytochrome c and AIF-1, as well as senescence pathways including upregulation of p21WAF1/Cip1. These pathways of irradiation-induced neuronal apoptosis may involve miR-711-dependent downregulation of pro-survival genes Akt and Ang-1. Accordingly, we demonstrated that inhibition of miR-711 attenuated degradation of Akt and Ang-1 mRNAs and reduced intrinsic apoptosis after neuronal irradiation; likewise, administration of Ang-1 was neuroprotective. Importantly, irradiation also downregulated two novel miR-711 targets, DNA-repair genes Rad50 and Rad54l2, which may impair DNA damage responses, amplifying the stimulation of apoptotic and senescence pathways and contributing to neurodegeneration. Inhibition of miR-711 rescued Rad50 and Rad54l2 expression after neuronal irradiation, enhancing DNA repair and reducing p53-dependent apoptotic and senescence pathways. Significantly, we showed that brain irradiation in vivo persistently elevated miR-711, downregulated its targets, including pro-survival and DNA-repair molecules, and is associated with markers of neurodegeneration, not only across the cortex and hippocampus but also specifically in neurons isolated from the irradiated brain. Our data suggest that irradiation-induced miR-711 negatively modulates multiple pro-survival and DNA-repair mechanisms that converge to activate neuronal intrinsic apoptosis and senescence. Using miR-711 inhibitors to block the development of these regulated neurodegenerative pathways, thus increasing neuronal survival, may be an effective neuroprotective strategy.

Human Nucleophosmin (NPM1) Perturbs Myeloid Development in Zebrafish in Vivo

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 308-308
Author(s):  
Niccolò Bolli ◽  
Elspeth Payne ◽  
Clemens Grabher ◽  
Adam Johnston ◽  
John Kanki ◽  
...  
Keyword(s):  
Cell Death ◽  
Stem Cell ◽  
Myeloid Cells ◽  
Genetic Alterations ◽  
Developmental Expression ◽  
In Vivo Models ◽  
Hematopoietic Stem ◽  
Cytoplasmic Transport ◽  
Dependent Cell

Abstract The most frequent genetic alterations in adult cases of Acute Myeloid Leukemia (AML) are mutations in the human nucleophosmin (hNPM1) gene. In about 30% of AMLs this nucleolar phosphoprotein is aberrantly localized to the cytoplasm (hNPMc) due to these mutations affecting the protein’s nuclear shuttling. hNPMc AMLs exhibit distinctive clinical and biological features that have led to its WHO classification as a distinct myeloid neoplasm. Despite its prominent association with AML, in vitro and in vivo models of hNPMc transformation in myeloid cells are lacking and its role in this process remains poorly understood. To further our understanding of hNPM function we are using the zebrafish vertebrate model system that is ideally suited for the in vivo analysis of cellular function and development during embryonic hematopoiesis. Importantly, the wide variety of blood cell types and key cellular factors regulating hematopoiesis are highly conserved between mammals and zebrafish. To investigate the in vivo role of hNPMc in hematopoiesis, we injected mRNAs encoding hNPM1wt and the leukemia-associated mutant hNPMc into one-cell stage zebrafish embryos. By fusing GFP to these hNPM proteins, we were able to follow the developmental expression of hNPM1 and its subcellular localization during embryogenesis. Analysis using confocal microscopy showed that NPMc is localized to the cell cytoplasm, while NPM1wt is found in nucleoli, as in human and mouse cells. These studies demonstrate the conservation of the nuclear-cytoplasmic transport functions of the human proteins in the zebrafish and further support its validity as a model to analyze and determine hNPM function. We also observed that hNPMc is expressed at far lower levels than its wild-type counterpart and is almost undetectable at 36hpf while hNPMwt continues to be expressed. Unlike mammals, two endogenous zebrafish NPM1 proteins were identified and named, zNpm1a and zNpm1b. Both zNpm1a and zNpm1b proteins are ubiquitously expressed in the embryo and demonstrated nucleolar localization. Expression of hNPMwt resulted in its colocalization with endogenous zNpm while hNPMc was able to bring about the export of both zebrafish proteins to the cytoplasm through heterotypic interactions. Co-immunoprecipitation experiments confirmed the interaction between human and zebrafish NPM1 proteins and zNpm1a and zNpm1b were both able to bind and co-immunoprecipitate with hNPM1 and hNPMc. These experiments suggest that transient hNPMc expression during zebrafish hematopoiesis may mimic its function in human leukemic blasts and provide clues to its functional role in AML. Comparable protein levels of either hNPMwt or hNPMc were expressed in embryos, confirmed by western blot at 22–24 hpf, and analyzed by whole mount in situ hybridization (WISH) using antisense RNA markers of specific hematopoietic lineages. Expression of hNPMc caused an increase in cMYB expression at 36 hpf, indicating an increase in the hematopoietic stem cell compartment. Furthermore, myeloid precursors (PU.1 at 22 hpf) also showed an increase upon hNPMc expression; however, mature myeloid cell (MPO and L-plastin at 26 hpf) levels were not increased relative to those in control hNPMwt injected embryos. Interestingly, the expression of hNPMc in p53 mutant embryos resulted in elevated levels of both PU.1 and MPO expressing cells, suggesting that hNPMc in zebrafish can activate p53 dependent cell cycle arrest, senescence or cell death in PU.1 cells prior to differentiation. These in vivo studies of hNPMc function during zebrafish hematopoietic differentiation suggest that hNPMc expression may increase the stem cell/ myeloid precursor compartment and can activate a p53 dependent cell death response in myeloid cells. Taking advantage of the zebrafish system in these continuing studies will further address how hNPMc expression may contribute to leukemogenesis.

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