MAPKs: new targets for neurodegeneration.
Neurodegenerative diseases remain a huge unmet pharmaceutical need. For some diseases such as Parkinson's disease, there are currently only palliative therapies, and for others such as Alzheimer's disease there are no proven therapies on the market that have any significant impact on disease progression. Recent work has suggested that cell death may play a key role in a number of neurodegenerative diseases, and halting this aberrant cell death may halt disease progression. Kinases identified in cell death pathways may be attractive targets for neurodegenerative diseases. In this review, the authors will focus on three families of related mitogen-activated protein kinases (MAPKs), namely, the extracellular signal-regulated protein kinases (ERKs), the c-Jun N-terminal kinases (JNKs) and the p38 MAPKs. The evidence for activation of each of these pathways in disease states and in models of neurodegenerative disorders will be examined. Effects of inhibitors, where available, will be discussed, and potential problems and side effects of kinase inhibitors as therapeutics will be addressed.
Harper
Sarah J
SJ
Department of Biochemistry & Molecular Biology, Neuroscience Research Centre, Merck, Sharp & Dohme Research Laboratories, Terlings Park, Harlow, Essex CM20 2QR, UK. sarah_harper@merck.com
Wilkie
Neil
N
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology; D002491:Central Nervous System Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy / Q000201:enzymology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000145:classification / Q000502:physiology; D008954:Models, Biological; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000201:enzymology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000201:enzymology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000145:classification / Q000502:physiology; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
D002491:Central Nervous System Agents; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases