Interplay between lysosomal, mitochondrial and death receptor pathways during manganese-induced apoptosis in glial cells
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 gr...
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todo:paper_03405761_v91_n9_p3065_Gorojod2023-10-03T15:25:46Z Interplay between lysosomal, mitochondrial and death receptor pathways during manganese-induced apoptosis in glial cells Gorojod, R.M. Alaimo, A. Porte Alcon, S. Saravia, F. Kotler, M.L. 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 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. Fil:Alaimo, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Porte Alcon, S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Kotler, M.L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_03405761_v91_n9_p3065_Gorojod |
| institution |
Universidad de Buenos Aires |
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I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 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 |
| topic_facet |
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 |
| description |
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. |
| format |
JOUR |
| author |
Gorojod, R.M. Alaimo, A. Porte Alcon, S. Saravia, F. Kotler, M.L. |
| author_facet |
Gorojod, R.M. Alaimo, A. Porte Alcon, S. Saravia, F. Kotler, M.L. |
| author_sort |
Gorojod, R.M. |
| title |
Interplay between lysosomal, mitochondrial and death receptor pathways during manganese-induced apoptosis in glial cells |
| title_short |
Interplay between lysosomal, mitochondrial and death receptor pathways during manganese-induced apoptosis in glial cells |
| title_full |
Interplay between lysosomal, mitochondrial and death receptor pathways during manganese-induced apoptosis in glial cells |
| title_fullStr |
Interplay between lysosomal, mitochondrial and death receptor pathways during manganese-induced apoptosis in glial cells |
| title_full_unstemmed |
Interplay between lysosomal, mitochondrial and death receptor pathways during manganese-induced apoptosis in glial cells |
| title_sort |
interplay between lysosomal, mitochondrial and death receptor pathways during manganese-induced apoptosis in glial cells |
| url |
http://hdl.handle.net/20.500.12110/paper_03405761_v91_n9_p3065_Gorojod |
| work_keys_str_mv |
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1807318535968391168 |