Sensitivity to Oxidative Stress in DJ-1-Deficient Dopamine Neurons: An ES- Derived Cell Model of Primary Parkinsonism

Abstract

The hallmark of Parkinson's disease (PD) is the selective loss of dopamine neurons in the ventral midbrain. Although the cause of neurodegeneration in PD is unknown, a Mendelian inheritance pattern is observed in rare cases, indicating a genetic factor. Furthermore, pathological analyses of PD substantia nigra have correlated cellular oxidative stress and altered proteasomal function with PD. Homozygous mutations in DJ-1 were recently described in two families with autosomal recessive Parkinsonism, one of which is a large deletion that is likely to lead to loss of function. Here we show that embryonic stem cells deficient in DJ-1 display increased sensitivity to oxidative stress and proteasomal inhibition. The accumulation of reactive oxygen species in toxin-treated DJ-1-deficient cells initially appears normal, but these cells are unable to cope with the consequent damage that ultimately leads to apoptotic death. Furthermore, we find that dopamine neurons derived from in vitro–differentiated DJ-1-deficient embryonic stem cells display decreased survival and increased sensitivity to oxidative stress. These data are consistent with a protective role for DJ-1, and demonstrate the utility of genetically modified embryonic stem cell–derived neurons as cellular models of neuronal disorders.

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…DJͲ1Ͳdeficient mice demonstrated hypersensitivity to MPTP and this was observed by increased dopaminergic neuronal loss and striatal denervation [276]. In embryonic cortical neurons, an increased sensitivity to oxidative stress and proteasomal inhibitionhas been also demonstrated, ending in apoptotic cell death [276,277]. All impairments were reversed by restitution of DJͲ1 expression.…”

Stimulation of vesicular monoamine transporter 2 activity by DJ-1 in SH-SY5Y cells

“…Deletion and point mutations of DJ-1 have been shown to be responsible for onset of familial Parkinson's disease, PARK7 [5]. DJ-1 is a multi-functional protein and plays roles in transcriptional regulation [8][9][10][11][12][13][14][15] and in modulation of signaling cascades [16][17][18][19][20] through protein-protein interaction, leading to anti-oxidative stress function [21][22][23]. Furthermore, we have reported that DJ-1 activated TH and DDC through direct binding to TH and DDC in an oxidative status of DJ-1-dependent manner [24] and that human DJ-1 activates TH gene expression in cultured human dopaminergic cells [15].…”

DJ-1 binds to mitochondrial complex I and maintains its activity

“…DJ-1 was first identified by our group as a novel oncogene product [1] and was later found to be a causative gene product of a familial form of PD, PARK7 [2]. DJ-1 plays roles in transcriptional regulation [3][4][5][6][7][8] and anti-oxidative stress reaction [9][10][11][12], and loss of its function is thought to affect the onset of PD. DJ-1 has three cysteines at amino acid numbers 46, 53 and 106 (C46, C53 and C106, respectively).…”

“…DJ-1 has three cysteines at amino acid numbers 46, 53 and 106 (C46, C53 and C106, respectively). Although oxidation of C106 is necessary for DJ-1 to exert its activity [11][12][13], further oxidation of C106 is thought to render DJ-1 inactive [14], and such oxidized DJ-1 has been observed in patients with the sporadic form of PD and Alzheimer disease [15,16].…”