Programmed cell death and new discoveries in the genetics of parkinsonism.
The concept that activation of cellular pathways of programmed cell death (PCD) may lead to the death of neurons has been an important hypothesis for adult neurodegenerative diseases. For Parkinson's disease (PD), up until now, the evidence for this hypothesis has largely been of two types: clear evidence of a role for PCD in neurotoxin models of the disease, and somewhat controversial evidence from human postmortem studies. With the rapid pace of discoveries in recent years of the genetic basis of PD, a new form of evidence has emerged. The prevailing concept of the role for PCD in PD has been that its mediators are 'downstream' effectors of more proximate and specific causes related to genetic or environmental factors. However, recent studies of three genes which cause autosomal recessive forms of parkinsonism, parkin, PTEN-induced kinase, and DJ-1, suggest that they may have more intimate relationships with the mediators of PCD and that loss-of-function mutations may result in an increased propensity for neurons to die. Intriguingly, independent studies of the function of these genes have suggested that they may share roles in regulating survival signaling pathways, such as those mediated by the survival signaling kinase Akt. Further elucidation of these relationships will have implications for the pathogenesis and neuroprotective treatment of PD.
Burke
Robert E
RE
Department of Neurology and Pathology, Columbia University, The College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. rb43@columbia.edu
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D018390:Gene Targeting / Q000379:methods / Q000639:trends; D006801:Humans; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D015398:Signal Transduction / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein