Mixed lineage kinase-c-jun N-terminal kinase signaling pathway: a new therapeutic target in Parkinson's disease.
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.
Silva
Robert M
RM
Department of Neurology, The College of Physicians and Surgeons, Columbia University, 650 West 168th Street, New York, NY 10032, USA.
Kuan
Chia-Yi
CY
Rakic
Pasko
P
Burke
Robert E
RE
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002227:Carbazoles / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008954:Models, Biological; D009410:Nerve Degeneration / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000627:therapeutic use; D010300:Parkinson Disease / Q000517:prevention & control; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D002227:Carbazoles; D007211:Indoles; D018696:Neuroprotective Agents; D016755:Proto-Oncogene Proteins c-jun; C106592:3,9-bis((ethylthio)methyl)-K-252a; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases