DJ-1 protects against dopamine toxicity

Abstract

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons. Dopamine is a highly toxic compound leading to generation of reactive oxygen species (ROS). DJ-1 mutations lead to early-onset inherited PD. Here, we show that DJ-1 protects against dopamine toxicity. Dopamine-exposure led to upregulation of DJ-1. Overexpression of DJ-1 increased cell resistance to dopamine toxicity and reduced intracellular ROS. Contrary effects were achieved when DJ-1 levels were reduced by siRNA. Similarly, in vivo striatal administration of 6-hydroxydopamine led to upregulation of DJ-1. Upregulation of DJ-1 was mediated by the MAP kinases pathway through activation of ERK 1, 2 in vitro and in vivo. Hence, oxidative stress, generated by free cytoplasmic dopamine, leads to upregulation of DJ-1 through the MAP kinases pathway. This mechanism elucidates how mutations in DJ-1 prompt PD and imply that modulation of DJ-1 may serve as a novel neuroprotective modality.

Cytosolic Sulfotransferase 1A3 Is Induced by Dopamine and Protects Neuronal Cells from Dopamine Toxicity

“…Induction of SULT1A1/3 Protects Neuronal-like Cells from Dopamine Toxicity-In the presence of serum, dopamine exhibits much less toxicity in human neuronal cells (42,43) compared with nonhuman cells, such as chick (44) or mouse (45) neurons. We hypothesized that this difference may be due to SULT1A3 induction during exposure to the catecholamine.…”

Retigeric acid B-induced mitophagy by oxidative stress attenuates cell death against prostate cancer cells in vitro

“…It is generally known that loss-offunction DJ-1 mutations can cause early-onset Parkinson's disease. DJ-1 acts as a redox-sensitive chaperone and a sensor for oxidative stress [7] ; it also protects cells against oxidative stress during neuronal injury [8,9] . Furthermore, DJ-1 protects several types of cancer cells, including leukemic [10] , lung carcinoma [11] , and breast cancer [12] cells, from oxidative stress-induced apoptosis.…”

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].…”