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Abstract:

Manganese (Mn) is an essential trace metal which plays a critical role in brain physiology by acting as a cofactor for several enzymes. However, upon overexposure, Mn preferentially accumulates within the basal ganglia leading to the development of a Parkinsonism known as Manganism. Data from our group have proved that Mn induces oxidative stress-mediated apoptosis in astrocytoma C6 cells. In the present study we described how cathepsins impact on different steps of each apoptotic cascade. Evidence obtained demonstrated that Mn generates lysosomal membrane permeabilization (LMP) and cathepsin release. Both cathepsins B (Ca-074 Me) and D (Pepstatin A) inhibitors as well as Bafilomycin A1 prevented caspases-3, -7, -8 and -9 activation, FasL upregulation, Bid cleavage, Δφm disruption and cytochrome c release. Results from in vivo studies showed that intrastriatal Mn injection increased cathepsin D levels from corpus striatum and substantia nigra pars compacta. Our results point to LMP and lysosomal cathepsins as key mediators in the apoptotic process triggered by Mn. These findings highlight the relevance of targeting the lysosomal pathway for Manganism therapy. © 2017, Springer-Verlag Berlin Heidelberg.

Registro:

Documento: Artículo
Título:Interplay between lysosomal, mitochondrial and death receptor pathways during manganese-induced apoptosis in glial cells
Autor:Gorojod, R.M.; Alaimo, A.; Porte Alcon, S.; Saravia, F.; 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
CONICET- Universidad de Buenos Aires, Instituto de Biologia y Medicina Experimental (IBYME), Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Laboratorio de Neurobiologia, Buenos Aires, Argentina
Palabras clave:Apoptosis; Cathepsins; Glia; Lysosomes; Manganese; Parkinsonism; bafilomycin A1; caspase 3; caspase 7; caspase 8; caspase 9; cathepsin; cathepsin B; cathepsin D; cytochrome c; death receptor; Fas ligand; manganese; pepstatin; protein Bid; Bid protein, rat; caspase 3; caspase 7; cathepsin D; Fas ligand; macrolide; manganese; protein Bid; Tnfsf6 protein, rat; animal cell; animal experiment; animal model; animal tissue; apoptosis; Article; controlled study; corpus striatum; cytosol; enzyme activation; enzyme release; glia cell; immunocytochemistry; immunohistochemistry; in vivo study; lysosome; lysosome membrane; male; membrane permeability; mitochondrion; molecular biology; nonhuman; oxidative stress; priority journal; protein cleavage; protein expression; protein transport; rat; substantia nigra pars compacta; upregulation; Western blotting; animal; apoptosis; drug effect; glia; lysosome; metabolism; mitochondrion; pathology; physiology; signal transduction; Sprague Dawley rat; tumor cell line; Animals; Apoptosis; BH3 Interacting Domain Death Agonist Protein; Caspase 3; Caspase 7; Cathepsin D; Cell Line, Tumor; Cytosol; Fas Ligand Protein; Lysosomes; Macrolides; Male; Manganese; Mitochondria; Neuroglia; Protein Transport; Rats, Sprague-Dawley; Signal Transduction
Año:2017
Volumen:91
Número:9
Página de inicio:3065
Página de fin:3078
DOI: http://dx.doi.org/10.1007/s00204-017-1936-7
Título revista:Archives of Toxicology
Título revista abreviado:Arch. Toxicol.
ISSN:03405761
CODEN:ARTOD
CAS:bafilomycin A1, 88899-55-2; caspase 3, 169592-56-7; caspase 7, 189258-14-8; caspase 8; caspase 9, 180189-96-2; cathepsin, 9004-08-4; cathepsin B, 9047-22-7; cathepsin D, 9025-26-7; cytochrome c, 9007-43-6, 9064-84-0; manganese, 16397-91-4, 7439-96-5; pepstatin, 26305-03-3, 39324-30-6; protein Bid, 260235-79-8; bafilomycin A1; BH3 Interacting Domain Death Agonist Protein; Bid protein, rat; Caspase 3; Caspase 7; Cathepsin D; Fas Ligand Protein; Macrolides; Manganese; Tnfsf6 protein, rat
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03405761_v91_n9_p3065_Gorojod

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Citas:

---------- APA ----------
Gorojod, R.M., Alaimo, A., Porte Alcon, S., Saravia, F. & Kotler, M.L. (2017) . Interplay between lysosomal, mitochondrial and death receptor pathways during manganese-induced apoptosis in glial cells. Archives of Toxicology, 91(9), 3065-3078.
http://dx.doi.org/10.1007/s00204-017-1936-7
---------- CHICAGO ----------
Gorojod, R.M., Alaimo, A., Porte Alcon, S., Saravia, F., Kotler, M.L. "Interplay between lysosomal, mitochondrial and death receptor pathways during manganese-induced apoptosis in glial cells" . Archives of Toxicology 91, no. 9 (2017) : 3065-3078.
http://dx.doi.org/10.1007/s00204-017-1936-7
---------- MLA ----------
Gorojod, R.M., Alaimo, A., Porte Alcon, S., Saravia, F., Kotler, M.L. "Interplay between lysosomal, mitochondrial and death receptor pathways during manganese-induced apoptosis in glial cells" . Archives of Toxicology, vol. 91, no. 9, 2017, pp. 3065-3078.
http://dx.doi.org/10.1007/s00204-017-1936-7
---------- VANCOUVER ----------
Gorojod, R.M., Alaimo, A., Porte Alcon, S., Saravia, F., Kotler, M.L. Interplay between lysosomal, mitochondrial and death receptor pathways during manganese-induced apoptosis in glial cells. Arch. Toxicol. 2017;91(9):3065-3078.
http://dx.doi.org/10.1007/s00204-017-1936-7