The pathogenesis of cell death in Parkinson's disease--2007.
A number of factors have been implicated in the pathogenesis of cell death in Parkinson's disease (PD). These include oxidative stress, mitochondrial dysfunction, inflammation, excitotoxicity, and apoptosis. While the precise pathogenic mechanism leading to neurodegeneration in PD is not known, there is considerable evidence suggesting that cell death occurs by way of a signal-mediated apoptotic process. PD is also characterized by intracellular proteinaceous inclusions or Lewy bodies. Proteolytic stress arises as a consequence of the excessive production of misfolded proteins, which exceed the capacity of the ubiquitin-proteasome system to degrade them. Recent genetic and laboratory studies support the possible relevance of proteolytic stress to both familial and sporadic forms of PD. Postmortem studies have shown that in the SNc of sporadic PD patients there are reduced levels of the alpha subunit of the 20S proteasome and reduced proteolytic enzyme activities. A determination as to the precise cause of cell death in PD, and the identification of specific targets for the development of drugs that might modify disease progression is one of the most critical goals in PD research. It is anticipated that over the next few years there will be a flurry of scientific activity examining the mechanism of cell death and putative neuroprotective interventions.
Olanow
C Warren
CW
Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA. warren.olanow@mssm.edu
D016923:Cell Death; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D016631:Lewy Bodies / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology; D018384:Oxidative Stress / Q000502:physiology; D010100:Oxygen / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D017354:Point Mutation / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D025801:Ubiquitin / Q000502:physiology; D051844:alpha-Synuclein / Q000378:metabolism
D025801:Ubiquitin; D051844:alpha-Synuclein; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex; D010100:Oxygen; D004298:Dopamine