[Parkinson disease: mechanisms of cell death]

Parkinson disease is a neurodegenerative disorder of aging characterized by a selective and progressive loss of dopaminergic neurons within the substantia nigra. The diagnosis of the disease is made when neuronal cell loss exceeds 50 p. 100 indicating that the degenerative process started well before the onset of the first clinical symptoms. Three populations of dopaminergic neurons seem to coexist in the substantia nigra of parkinsonian patients; (1) senescent neurons that are still spared by the pathological process; (2) sick neurons exhibiting generally a preserved morphology but showing evidence of biochemical and metabolic abnormalities; (3) neurons which have entered into a final state of agony and exhibit the hallmarks of apoptosis, a controlled form of cell death that requires the activation of a particular type of proteases, caspases. In the inherited forms of the disease that are caused by mutations of genes encoding the Parkin, alpha-synuclein and UCHL-1 proteins, the degenerative process results from the dysfunction of an enzymatic complex of proteolysis, the proteasome. This probably leads to the intracellular accumulation of abnormal proteins that become deleterious for dopaminergic neurons. In the sporadic forms of the disease that are the most frequent, causes of the cell demise remain still unknown but neurodegeneration might also result from a decreased activity of the proteasome. A defect in the detoxification of reactive oxygen species or an energy failure caused by inhibition of the mitochondrial respiratory chain, at the complex I level, are other hypothesis that are frequently mentioned. Finally, activated glial cells (astrocytes and microglia) located around the degenerating dopaminergic neurons might also intervene in the mechanism of degeneration by perpetuating or even amplifying the primary neuronal insult. Proinflammatory cytokines acting on cell death membrane receptors and diffusable messengers such as nitric oxide could be part of this process.