Mitochondrial Cell Death Control in Familial Parkinson Disease

Parkinson 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 a-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 identified—annihilate or reduce the kinase activity of the protein. A study by Julia W. Pridgeon (Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, 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.