Intracellular signalling pathways in dopamine cell death and axonal degeneration.
The pathways of programmed cell death (PCD) are now understood in extraordinary detail at the molecular level. Although much evidence suggests that they are likely to play a role in Parkinson's disease (PD), the precise nature of that role remains unknown. Two pathways of cell death that are especially well characterized are cyclin-dependent kinase 5-mediated phosphorylation of myocyte enhancer factor 2 and the mitogen-activated protein kinase signalling cascade. Although blockade of these pathways in animals has achieved a truly remarkable degree of neuroprotection of the neuron cell soma, it has not achieved protection of axons. Thus, there is a need to explore beyond the canonical pathways of PCD and investigate mechanisms of axon destruction. We also need to move beyond the narrow classic concept that the mechanisms of PCD are activated exclusively 'downstream', following cellular injury. Studies in the genetics of PD suggest that in some forms of the disease, activation may be an early 'upstream' event. Additionally, recent observations suggest that cell death in some contexts may not be initiated by injury, but instead by a failure of intrinsic cell survival signalling. These new points of view offer new opportunities for molecular targeting.
Burke
Robert E
RE
Department of Neurology, Columbia University, New York, NY, USA. rb43@columbia.edu
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001369:Axons / Q000473:pathology / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000473:pathology* / Q000502:physiology; D015513:Oncogene Proteins / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D000099202:PTEN-Induced Putative Kinase
D004298:Dopamine; D051100:Glial Cell Line-Derived Neurotrophic Factor; D047908:Intracellular Signaling Peptides and Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D015513:Oncogene Proteins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000099202:PTEN-Induced Putative Kinase; C495280:LRRK2 protein, human; C105131:PARK7 protein, human