Activation of ataxia telangiectasia muted under experimental models and human Parkinson’s disease |
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Authors: | Antoni Camins Javier G Pizarro Daniel Alvira Javier Gutierrez-Cuesta Aurelio Vazquez de la Torre Jaume Folch Francesc X Sureda Ester Verdaguer Felix Junyent Joaquín Jordán Isidre Ferrer Mercè Pallàs |
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Institution: | 1. Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universitat de Barcelona, Nucli Universitari de Pedralbes, 08028, Barcelona, Spain 2. Unitat de Bioquimica, Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, C./St. Lloren? 21, 43201, Reus (Tarragona), Spain 3. Grupo de Neurofarmacología, Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha, Albacete, Spain 4. Institut de Neuropatologia, IDIBELL - Hospital Universitari de Bellvitge, Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universitat de Barcelona, Hospitalet de Llobregat, Barcelona, Spain
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Abstract: | In the present study we demonstrated that neurotoxin MPP+-induced DNA damage is followed by ataxia telangiectasia muted (ATM) activation either in cerebellar granule cells (CGC) or in B65 cell line. In CGC, the selective ATM inhibitor KU-55933 showed neuroprotective effects against MPP+-induced neuronal cell loss and apoptosis, lending support to the key role of ATM in experimental models of Parkinson’s disease. Likewise, we showed that knockdown of ATM levels in neuroblastoma B65 cells using an ATM-specific siRNA attenuates the phosphorylation of retinoblastoma protein without affecting other cell-cycle proteins involved in the G0/G1 cell-cycle phase. Moreover, we demonstrated DNA damage, in human brain samples of PD patients. These findings support a model in which MPP+ leads to ATM activation with a subsequent DNA damage response and activation of pRb. Therefore, this study demonstrates a new link between DNA damage by MPP+ and cell-cycle re-entry through retinoblastoma protein phosphorylation. |
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