Antioxidants protect PINK1 -dependent dopaminergic neurons in Drosophila

Abstract

Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. Mutations in the PINK1 gene are linked to the autosomal recessive early onset familial form of PD. The physiological function of PINK1 and pathological abnormality of PDassociated PINK1 mutants are largely unknown. We here show that inactivation of Drosophila PINK1 (dPINK1) using RNAi results in progressive loss of dopaminergic neurons and in ommatidial degeneration of the compound eye, which is rescued by expression of human PINK1 (hPINK1). Expression of human SOD1 suppresses neurodegeneration induced by dPINK1 inactivation. Moreover, treatment of dPINK1 RNAi flies with the antioxidants SOD and vitamin E significantly inhibits ommatidial degeneration. Thus, dPINK1 plays an essential role in maintaining neuronal survival by preventing neurons from undergoing oxidative stress, thereby suggesting a potential mechanism by which a reduction in PINK1 function leads to PD-associated neurodegeneration.neurodegeneration ͉ oxidative stress ͉ Parkinson's disease ͉ SOD1

Antioxidants put Parkinson flies back in the PINK

“…One explanation for this variation in phenotype is that genetic background may play an important role in the severity and͞or penetrance of the dPINK1 phenotype. Perhaps the degree of baseline oxidative damage depends on genetic background, which would be consistent with the finding by Wang et al (6) that antioxidants can protect against even the most severe dPINK1 loss-of-function phenotype. It also has been suggested that the environment and genetic background similarly play a key role in the age of onset and severity of PD in humans.…”

“…The Wang et al (6) study complements recent parallel reports (7)(8)(9) examining the phenotypes of dPINK1 mutant flies to provide new insights into the integrated function of cytoplasmic and mitochondrial proteins in the etiology of PD. An important puzzle in the etiology of PD is that it seems to involve both cytoplasmic and mitochondrial functions, yet it is unclear how these functions might be linked.…”

“…PINK1 and DJ-1 appear to function in the same pathway as Parkin, which encodes an E3 ubiquitin ligase that is thought to function primarily in the cytoplasm, presumably to target specific protein targets for degradation or modified function͞local-ization (11). Parallel studies to those of Wang et al (6) revealed that the loss of dPINK1 function resulted in a set of neuronal and flight muscle phenotypes very similar to those present in dParkin mutant flies (7)(8)(9). Although the protein targets regulated by Parkin that are involved in PD are not known for certain, one clear candidate is ␣-synuclein because elevated levels of this protein are observed in Parkin mutant cells and because at least one form of ␣-synuclein is a substrate for Parkin-mediated ubiquitination (12).…”

“…PINK1͞DJ-1 therefore may influence the transcription and͞or translation of Parkin, although it is unclear whether this effect would be direct or indirect. This study by Wang et al (6) further indicates that antioxidants also act downstream of PINK1 and suggests that PINK1 may play a role in sensing oxidative damage rather than in responding to it. In line with this view, dPINK1 mutants are hypersensitive to agents causing oxidative damage such as rotenone or paraquot (8).…”

“…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 and retinal neurons, which are phenotypes similar to the pathological changes in human PD.…”