Antioxidants put Parkinson flies back in the PINK

Parkinson's disease (PD) is the second most frequent neurodegenerative disease, affecting ≈1% of people above age 50. PD is clinically characterized by age-dependent uncontrollable tremor, postural imbalance, slowness of movement, and rigidity. The most salient pathological feature of PD is a progressive loss of dopaminergic neurons in the substantia nigra region of the midbrain (1, 2). The majority of PD cases are sporadic; however, ≈10–15% are familial, and mutations in at least six loci are known to cause PD. Several of these PD genes are associated with ubiquitin-mediated protein degradation and the abnormal accumulation of proteins such as α-synuclein in cytoplasmic aggregates known as Lewy bodies. There is also evidence that oxidative stress and defects in mitochondrial function, particularly in complex I, may contribute to PD (3). Exposure of humans or mice to the environmental toxins MPTP, paraquot, or rotenone results in acute and irreversible parkinsonism. These toxins impair mitochondrial function and consequently increase free radical production and oxidative stress. The age-dependent and progressive nature of the disease, as well as the fact that most PD cases are sporadic, suggest that environmental factors also play important roles in the pathogenesis of the disease. A favored hypothesis of PD pathogenesis is that genetic changes sensitize dopaminergic neurons to intrinsic or extrinsic insults, leading to the eventual loss of these neurons and to parkinsonism. Previous studies have shown that the fruitfly Drosophila melanogaster is a suitable model for analyzing the function of genes involved in PD (4, 5). In this issue of PNAS, Wang et al. (6) expand the analysis of PD in Drosophila to examine the role of PTEN-Induced Kinase 1 (PINK1), a mitochondrial protein. They find that reducing the activity of the single Drosophila homolog of PINK1 (dPINK1) induces a progressive loss of dopaminergic neurons …

*E-mail: ebier{at}ucsd.edu