title: Interplay between lysosomal, mitochondrial and death receptor pathways during manganese-induced apoptosis in glial cells.
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.
authors.affiliation: 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.
authors.forename: R M
authors.initials: RM
authors.lastname: Gorojod
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Alaimo
authors.affiliation: 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.
authors.forename: S
authors.initials: S
authors.lastname: Porte Alcon
authors.affiliation: 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.
authors.forename: F
authors.initials: F
authors.lastname: Saravia
authors.affiliation: 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. moniquekotler@gmail.com.
authors.forename: M L
authors.identifier: http://orcid.org/0000-0002-3555-7621
authors.initials: ML
authors.lastname: Kotler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D045744:Cell Line, Tumor; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D008345:Manganese / Q000493:pharmacokinetics / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494816:Bid protein, rat; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D018942:Macrolides; D008345:Manganese; C040929:bafilomycin A1; D053148:Caspase 3; D053179:Caspase 7; D002402:Cathepsin D
keywords: Apoptosis; Cathepsins; Glia; Lysosomes; Manganese; Parkinsonism