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Activation of ataxia telangiectasia muted under experimental models and human Parkinson’s disease

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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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Acknowledgments

This study was supported by grants from Spain’s “Ministerio de Educación y Ciencia” SAF2009-13093 (MP), SAF2008-05143-C03-1 (J.J.), the “Fondo de Investigación Sanitaria”, and the “Instituto de Salud Carlos III” PI080400 and PS09/01789 (FEDER FOUNDS). 610RT0405 from Programa Iberoamericano de Ciencia y Tecnologia para el Desarrollo (CYTED). We would like to thank the “Generalitat de Catalunya” for supporting the research groups (2009/SGR00853) and the “Fundació la Marató TV3” (063230). Ester Verdaguer holds a “Beatriu de Pinós” postdoctoral contract, awarded by the “Generalitat de Catalunya”. We wish to thank the Language Assessment Service of the University of Barcelona for revising the manuscript.

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Authors and Affiliations

  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

    Antoni Camins, Javier G. Pizarro, Daniel Alvira, Javier Gutierrez-Cuesta, Aurelio Vazquez de la Torre, Ester Verdaguer, Felix Junyent & Mercè Pallàs

  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. Llorenç 21, 43201, Reus (Tarragona), Spain

    Jaume Folch, Francesc X. Sureda & Felix Junyent

  3. Grupo de Neurofarmacología, Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha, Albacete, Spain

    Joaquín Jordán

  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

    Isidre Ferrer

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  1. Antoni Camins
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Camins, A., Pizarro, J.G., Alvira, D. et al. Activation of ataxia telangiectasia muted under experimental models and human Parkinson’s disease. Cell. Mol. Life Sci. 67, 3865–3882 (2010). https://doi.org/10.1007/s00018-010-0408-5

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