Mixed lineage kinase–c-jun N-terminal kinase signaling pathway: A new therapeutic target in Parkinson's disease

Authors

  • Robert M. Silva PhD,

    1. Department of Neurology, The College of Physicians and Surgeons, Columbia University, New York, New York, USA
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  • Chia-Yi Kuan PhD,

    1. Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati Ohio, USA
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  • Pasko Rakic MD, PhD,

    1. Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, USA
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  • Robert E. Burke MD

    Corresponding author
    1. Department of Neurology, The College of Physicians and Surgeons, Columbia University, New York, New York, USA
    2. Department of Pathology, The College of Physicians and Surgeons, Columbia University, New York, New York, USA
    • Department of Neurology, Room 308, Black Building, Columbia University, 650 West 168th Street, New York, NY 10032
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Abstract

There is growing evidence that the molecular pathways of programmed cell death play a role in neurodegenerative disease, including Parkinson's disease, so there has been increased interest in them as therapeutic targets for the development of neuroprotective strategies. One pathway of cell death that has attracted particular attention is the mixed lineage kinase (MLK) –c-jun N-terminal kinase (JNK) signaling cascade, which leads to the phosphorylation and activation of the transcription factor c-jun. There is much evidence, from in vitro and in vivo studies, that this cascade can mediate cell death. In addition, there is evidence that it is operative upstream in the death process. It is possible that abrogation of this pathway may forestall death before irreversible cellular injury. One class of compounds that has shown promise for their ability to block cell death by inhibiting this cascade are the inhibitors of the MLKs, which are upstream in the activation of c-jun. One of these compounds, CEP1347, is now in a Phase II/III clinical trial for neuroprotection in PD. Whether this trial is successful or not, this signaling cascade is likely to be a focus of future therapeutic development. This review, therefore, outlines the principles of signaling within this kinase pathway, and the evidence for its role in cell death. We review the evidence that inhibition of the MLKs can prevent dopamine neuron cell death and the degeneration of their axons. These studies suggest important future directions for the development of therapies that will target this important cell death pathway. © 2005 Movement Disorder Society

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