Mitochondrial Cell Death Control in Familial Parkinson Disease

P arkinson disease (PD) is the most frequent neurodegenerative disorder, affecting about 1% of people over 50 years old. It is caused by the progressive loss of dopaminergic (DA) neurons, accompanied by the accumulation of Lewy bodies, which are abnormal structures inside nerve cells that contain proteins such as α-synuclein, Parkin, and components of the ubiquitin proteasomal pathway (a cellular-degradation pathway). Patients are usually treated with levodopa, and although the drug initially improves motor symptoms, many patients later develop a range of abnormal or uncontrolled muscle movements, called dyskinesias. More than 90% of PD cases are sporadic, but rare genetic forms may yield invaluable information on the pathogenesis of both familial and spontaneous PD. After mutations affecting Parkin, mutations in PINK1 (PTEN-induced putative kinase 1) are the second-most common cause of autosomal recessive PD (where both parents must contribute a defective gene for PD to arise in the offspring). Point or truncation mutations in PINK1 produce PD with a broad phenotypic spectrum, from early-onset with atypical features to typical late-onset PD. Pathogenic PINK1 mutations—of which about 20 have been identifi ed—annihilate or reduce the kinase activity of the protein. A study United States) and colleages published in this issue of PLoS Biology shows that the failure of PINK1 to phosphorylate one particular substrate, TRAP1, can sensitize cells to the lethal effects of reactive oxygen species. Chemicals that inhibit the mitochondrial electron transport complex I or that elicit production of reactive oxygen species can induce PD in humans, suggesting that mitochondria, which not only produce cellular energy but also control cell death, play a major role in human PD [1]. For both neurons and non-neuronal cells, mitochondrial membranes are the battleground on which opposing signals combat to seal the cell's fate by mitochondrial membrane permeabilization (MMP). Factors that regulate MMP, include the pro-and anti-apoptotic members of the Bcl-2 family, proteins from the mitochondrial permeability transition pore complex (PTPC), and a host of interacting partners. Once MMP occurs, hydrolases and activators of caspases are released. The destructive action of these enzymes, as well as the cessation of the vital bioenergetic and redox functions of mitochondria, fi nally cause cell death, meaning that mitochondria coordinate the ultimate stage of cellular demise [2]. PINK1 localizes to mitochondria, and experiments in the fruit fl y (Drosophila melanogaster) show that PINK1 and DJ1 (another protein that when mutated causes a genetic form of PD) act together …