Ablation of serum response factor in dopaminergic neurons exacerbates susceptibility towards MPTP-induced oxidative stress

Authors

  • Claus Rieker,

    1. Division of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany
    2. Novartis Institute for BioMedical Research, Novartis Pharma AG, Basel, Switzerland
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  • Andreas Schober,

    1. Department of Molecular Embryology, Institute of Anatomy and Cell Biology II, University of Freiburg, Freiburg, Germany
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  • Ainhoa Bilbao,

    1. Department of Psychopharmacology, Central Institute of Mental Health, Mannheim, Germany
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  • Günther Schütz,

    1. Division of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany
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  • Jan Rodriguez Parkitna

    1. Division of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany
    2. Department of Neuropharmacology, Institute of Pharmacology of the Polish Academy of Sciences, Cracow, Poland
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Dr G. Schütz, as above.
E-mail: g.schuetz@dkfz.de

Abstract

The high susceptibility of dopaminergic (DA) neurons to cellular stress is regarded as a primary cause of Parkinson’s disease. Here we investigate the role of the serum response factor (SRF), an important regulator of anti-apoptotic responses, for the survival of DA neurons in mice. We show that loss of SRF in DA neurons does not affect their viability and does not influence dopamine-dependent behaviors. However, ablation of SRF causes exacerbated sensitivity to 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP), leading to significantly greater loss of DA neurons in the substantia nigra, compared with DA neurons located in the ventral tegmental area. In addition, loss of SRF decreases levels of the anti-apoptotic proteins brain-derived neurotrophic factor (BDNF) and Bcl-2, a plausible underlying cause of increased sensitivity to oxidative stress. These observations support the notion that dysfunction of the SRF-activating mitogen-associated kinase pathway may be part of Parkinson’s disease etiology.

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