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G1/S Cell Cycle Checkpoint Dysfunction in Lymphoblasts from Sporadic Parkinson’s Disease Patients

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Abstract

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease among aging individuals, affecting greatly the quality of their life. However, the pathogenesis of Parkinson’s disease is still incompletely understood to date. Increasing experimental evidence suggests that cell cycle reentry of postmitotic neurons precedes many instances of neuronal death. Since cell cycle dysfunction is not restricted to neurons, we investigated this issue in peripheral cells from patients suffering from sporadic PD and age-matched control individuals. Here, we describe increased cell cycle activity in immortalized lymphocytes from PD patients that is associated to enhanced activity of the cyclin D3/CDK6 complex, resulting in higher phosphorylation of the pRb family protein and thus, in a G1/S regulatory failure. Decreased degradation of cyclin D3, together with increased p21 degradation, as well as elevated levels of CDK6 mRNA and protein were found in PD lymphoblasts. Inhibitors of cyclin D3/CDK6 activity like sodium butyrate, PD-332991, and rapamycin were able to restore the response of PD cells to serum stimulation. We conclude that lymphoblasts from PD patients are a suitable model to investigate cell biochemical aspects of this disease. It is suggested that cyclin D3/CDK6-associated kinase activity could be potentially a novel therapeutic target for the treatment of PD.

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Acknowledgments

This work has been supported by grants from Ministerio de Economía y Competitividad (SAF2011-28603) and Fundación Ramón Areces to AMR, and Fundación Neurociencias y Envejecimiento to JAM. We would like to thank to all patients, their families, and clinicians involved in this study. The skillful technical assistance of Eduardo Parrilla is greatly appreciated.

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Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain

    Noemí Esteras, Carolina Alquézar, Fernando Bartolomé, Ana de la Encarnación & Ángeles Martín-Requero

  2. Department of Neurology, Hospital 12 de Octubre, Avda. de Córdoba s/n, 28041, Madrid, Spain

    Félix Bermejo-Pareja & José Antonio Molina

  3. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

    Félix Bermejo-Pareja & José Antonio Molina

  4. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain

    Carolina Alquézar & Ángeles Martín-Requero

  5. Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK

    Noemí Esteras

  6. Neuroscience Laboratory, Research Institute, Hospital 12 de Octubre, Avda. de Córdoba s/n, 28041, Madrid, Spain

    Fernando Bartolomé

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  1. Noemí Esteras
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Correspondence to Ángeles Martín-Requero.

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Esteras, N., Alquézar, C., Bartolomé, F. et al. G1/S Cell Cycle Checkpoint Dysfunction in Lymphoblasts from Sporadic Parkinson’s Disease Patients. Mol Neurobiol 52, 386–398 (2015). https://doi.org/10.1007/s12035-014-8870-y

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  • DOI: https://doi.org/10.1007/s12035-014-8870-y

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