Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling

Abstract

Parkinson's disease ͉ PI3K͞PTEN͞Akt signaling ͉ reactive oxygen species P arkinson's disease (PD) is the most common movement disorder and the second most common neurodegenerative disease. The movement abnormality in PD arises from deficiency of brain dopamine (DA) contents and the degeneration of dopaminergic neurons in the substantia nigra. The most common forms of PD are sporadic with no known cause. Nevertheless, postmortem studies have identified common features associated with sporadic PD, including defects in mitochondrial complex I function, oxidative damage, and abnormal protein aggregation (1).The contribution of genetic factors in the pathogenesis of PD, although initially controversial, has been firmly established by recent human genetic studies. At least 10 distinct loci (PARK1 to -11) have been linked to rare familial forms of PD (2). It is anticipated that understanding the molecular lesions associated with these familial PD (FPD) genes will shed light on the pathogenesis of the sporadic forms of the disease. To date, five unequivocal FPD genes have been molecularly cloned. These include ␣-Synuclein (␣-Syn), Parkin, DJ-1, PINK-1, and dardarin. Biochemical and biophysical studies of ␣-Syn and Parkin have primarily linked dysfunction of these genes to aberrant protein folding and ubiquitin-proteasome dysfunction. Intriguingly, in vivo genetic and in vitro cell culture studies have revealed their connection to mitochondrial dysfunction and oxidative stress, reinforcing the involvement of these processes in PD pathogenesis in general (3).DJ-1 encodes a conserved protein belonging to the ThiJ͞PfpI͞ DJ-1 superfamily. The exact molecular function of DJ-1 is still unclear. Human DJ-1 was initially discovered as a candidate oncoprotein that could transform cells in cooperation with activated ras (4), and it was later found as a component of an RNA-binding protein complex and was associated with male infertility (4-6). Under oxidative stress conditions, DJ-1 was modified by oxidation, and the modified form associated with mitochondria in cultured cells (7-10). Knocking down DJ-1 expression with small interfering RNA (siRNA) resulted in susceptibility to oxidative stress, endoplasmic reticulum stress, and proteasome inhibition (11). Recent analyses of DJ-1 knockout mice have shed light on the physiological function of DJ-1 in mammals. DJ-1-deficient mice were found to have nigrostriatal dopaminergic dysfunction, motor deficits, and hypersensitivity to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress stimuli (12)(13)(14). In mammalian cells, DJ-1 was found to regulate the phosphorylation status of protein kinase B (PKB)͞Akt through the tumor suppressor PTEN (15). The relevance of this novel finding of DJ-1 function to PD pathogenesis remains to be explored.As an alternative approach to understanding the role of DJ-1 dysfunction in PD pathogenesis, we have used Drosophila as a model system. We inhibited the function of a Drosophila DJ-1 homologue (DJ-1A) by transgenic RN...

Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

“…Although the precise cellular distribution of the PD protein DJ-1 is unsettled, it has been shown to protect against neuronal apoptosis associated with oxidative stress, possibly by functioning as a redoxsensitive co-transcriptional activator [1,65]. DJ-1-deficient mice are hypersensitive to MPTP and oxidative stress [10], and inhibition of DJ-1A function in Drosophila by RNA interference (RNAi) results in a number of defects, including hypersensitivity to oxidative stress, degeneration of dopaminergic neurons and impaired phosphatidylinositol 3-kinase (PI3K)/Akt signaling [66]. Interestingly, the same authors also observed impaired PI3K/Akt signaling in parkin RNAi transgenic flies, hinting at a common pathway in the pathogenesis of these PD genes [66].…”

“…DJ-1-deficient mice are hypersensitive to MPTP and oxidative stress [10], and inhibition of DJ-1A function in Drosophila by RNA interference (RNAi) results in a number of defects, including hypersensitivity to oxidative stress, degeneration of dopaminergic neurons and impaired phosphatidylinositol 3-kinase (PI3K)/Akt signaling [66]. Interestingly, the same authors also observed impaired PI3K/Akt signaling in parkin RNAi transgenic flies, hinting at a common pathway in the pathogenesis of these PD genes [66].…”

Tumours and tremors: how PTEN regulation underlies both

“…Significantly, this hypersensitivity to oxidative stress is also seen in the neurons of dj-1-deficient mice (Kim et al, 2005b). In both organisms, the increased susceptibility to oxidative stress can be rescued by activation of the PI3 0 K pathway (Kim et al, 2005b;Meulener et al, 2005;Yang et al, 2005). Other work has implicated DJ-1 as a sensor of reactive oxygen species and as a molecular chaperone (Shendelman et al, 2004), and DJ-1 may be able to influence the protein stability or oxidative state of elements of the PI3 0 K pathway.…”

“…Firstly, during tumorigenesis, the degradation of p27 kip1 can be driven by either PTEN or UCH-L1 (Caballero et al, 2002;Viglietto et al, 2002). Secondly, deletions of the Parkin gene in Drosophila result in PKB/Akt activation (Yang et al, 2005). Thirdly, PINK1, which encodes a kinase downregulated in the absence of PTEN, has been identified as the sixth locus (PARK6) associated with familial PD (West et al, 2005).…”

“…The biochemistry of the neurodegeneration in PD points to mitochondrial oxidative stress as the mechanism driving neuronal death in the SNpc. In Drosophila, an siRNAinduced reduction of DJ-1 causes neurons to become hypersensitive to oxidative stress, and these flies show neurodegeneration that is exacerbated by coexpression of PTEN (Yang et al, 2005). Significantly, this hypersensitivity to oxidative stress is also seen in the neurons of dj-1-deficient mice (Kim et al, 2005b).…”