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Abstract:

Microglia, the brain resident immune cells, play prominent roles in immune surveillance, tissue repair and neural regeneration. Despite these pro-survival actions, the relevance of these cells in the progression of several neuropathologies has been established. In the context of manganese (Mn) overexposure, it has been proposed that microglial activation contributes to enhance the neurotoxicity. However, the occurrence of a direct cytotoxic effect of Mn on microglial cells remains controversial. In the present work, we investigated the potential vulnerability of immortalized mouse microglial cells (BV-2) toward Mn 2+ , focusing on the signaling pathways involved in cell death. Evidence obtained showed that Mn 2+ induces a decrease in cell viability which is associated with reactive oxygen species (ROS) generation. In this report we demonstrated, for the first time, that Mn 2+ triggers regulated necrosis (RN) in BV-2 cells involving two central mechanisms: parthanatos and lysosomal disruption. The occurrence of parthanatos is supported by several cellular and molecular events: (i) DNA damage; (ii) AIF translocation from mitochondria to the nucleus; (iii) mitochondrial membrane permeabilization; and (iv) PARP1-dependent cell death. On the other hand, Mn 2+ induces lysosomal membrane permeabilization (LMP) and cathepsin D (CatD) release into the cytosol supporting the lysosomal disruption. Pre-incubation with CatB and D inhibitors partially prevented the Mn 2+ -induced cell viability decrease. Altogether these events point to lysosomes as players in the execution of RN. In summary, our results suggest that microglial cells could be direct targets of Mn 2+ damage. In this scenario, Mn 2+ triggers cell death involving RN pathways. © 2018 IBRO

Registro:

Documento: Artículo
Título:Regulated Necrosis Orchestrates Microglial Cell Death in Manganese-Induced Toxicity
Autor:Porte Alcon, S.; Gorojod, R.M.; Kotler, M.L.
Filiación:CONICET-Universidad de Buenos Aires, Instituto de Química Biológica Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Laboratorio de Disfunción Celular en Enfermedades Neurodegenerativas y Nanomedicina, Buenos Aires, Argentina
Palabras clave:lysosomes, regulated necrosis; manganese; Manganism; microglia; parthanatos; cathepsin D; manganese; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1; reactive oxygen metabolite; manganese; animal cell; apoptosis; Article; cell death; cell disruption; cell structure; cell viability; DNA damage; genotoxicity; human; human cell; lysosome; microglia; MTT assay; nonhuman; priority journal; signal transduction; animal; cell death; cell survival; drug effect; metabolism; microglia; mitochondrion; mouse; necrosis; Animals; Apoptosis; Cell Death; Cell Survival; Lysosomes; Manganese; Mice; Microglia; Mitochondria; Necrosis; Reactive Oxygen Species
Año:2018
Volumen:393
Página de inicio:206
Página de fin:225
DOI: http://dx.doi.org/10.1016/j.neuroscience.2018.10.006
Título revista:Neuroscience
Título revista abreviado:Neuroscience
ISSN:03064522
CODEN:NRSCD
CAS:cathepsin D, 9025-26-7; manganese, 16397-91-4, 7439-96-5; Manganese; Reactive Oxygen Species
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03064522_v393_n_p206_PorteAlcon

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Citas:

---------- APA ----------
Porte Alcon, S., Gorojod, R.M. & Kotler, M.L. (2018) . Regulated Necrosis Orchestrates Microglial Cell Death in Manganese-Induced Toxicity. Neuroscience, 393, 206-225.
http://dx.doi.org/10.1016/j.neuroscience.2018.10.006
---------- CHICAGO ----------
Porte Alcon, S., Gorojod, R.M., Kotler, M.L. "Regulated Necrosis Orchestrates Microglial Cell Death in Manganese-Induced Toxicity" . Neuroscience 393 (2018) : 206-225.
http://dx.doi.org/10.1016/j.neuroscience.2018.10.006
---------- MLA ----------
Porte Alcon, S., Gorojod, R.M., Kotler, M.L. "Regulated Necrosis Orchestrates Microglial Cell Death in Manganese-Induced Toxicity" . Neuroscience, vol. 393, 2018, pp. 206-225.
http://dx.doi.org/10.1016/j.neuroscience.2018.10.006
---------- VANCOUVER ----------
Porte Alcon, S., Gorojod, R.M., Kotler, M.L. Regulated Necrosis Orchestrates Microglial Cell Death in Manganese-Induced Toxicity. Neuroscience. 2018;393:206-225.
http://dx.doi.org/10.1016/j.neuroscience.2018.10.006