The Parkinson's disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis

Abstract

Mutations in the DJ-1 gene cause early-onset autosomal recessive Parkinson's disease (PD), although the role of DJ-1 in the degeneration of dopaminergic neurons is unresolved. Here we show that the major interacting-proteins with DJ-1 in dopaminergic neuronal cells are the nuclear proteins p54nrb and pyrimidine tract-binding protein-associated splicing factor (PSF), two multifunctional regulators of transcription and RNA metabolism. PD-associated DJ-1 mutants exhibit decreased nuclear distribution and increased mitochondrial localization, resulting in diminished co-localization with co-activator p54nrb and repressor PSF. Unlike pathogenic DJ-1 mutants, wild-type DJ-1 acts to inhibit the transcriptional silencing activity of the PSF. In addition, the transcriptional silencer PSF induces neuronal apoptosis, which can be reversed by wild-type DJ-1 but to a lesser extent by PD-associated DJ-1 mutants. DJ-1-specific small interfering RNA sensitizes cells to PSF-induced apoptosis. Both DJ-1 and p54nrb block oxidative stress and mutant alpha-synuclein-induced cell death. Thus, DJ-1 is a neuroprotective transcriptional co-activator that may act in concert with p54nrb and PSF to regulate the expression of a neuroprotective genetic program. Mutations that impair the transcriptional co-activator function of DJ-1 render dopaminergic neurons vulnerable to apoptosis and may contribute to the pathogenesis of PD.

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 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD

“…DJ-1 also functions as a transrepressor of a key tumor suppressor, PTEN (phosphatase and tensin homolog on chromosome 10), to regulate c-Myc and the catalytic unit of the telomerase complex, human telomerase reverse transcriptase (Sitaram et al, 2009). It contributes to cell survival by interacting with p54nrb to inhibit the silencing activity of pyrimidine tract-binding protein-associated splicing factor (Xu et al, 2005) or by regulating androgen receptor transcriptional activity (Takahashi et al, 2001;Niki et al, 2003;Tillman et al, 2007). Recently, DJ-1 was found to repress p53 (Bretaud et al, 2007;Fan et al, 2008a, b;Giaime et al, 2010).…”

Transduced Tat-DJ-1 Protein Protects against Oxidative Stress-Induced SH-SY5Y Cell Death and Parkinson Disease in a Mouse Model

“…DJ-1 is conserved in bacteria, plants, animals, and humans (Lucas and Marin, 2007). It is well known that DJ-1 has multiple functions including anti-oxidant and chaperone functions associated with PD pathogenesis (Menzies et al, 2005;Xu et al, 2005;Zhou et al, 2006). However, DJ-1 deficiency or loss-of-function leads to oxidative stressinduced cell death in vitro and in vivo (Chen et al, 2005;Goldberg et al, 2005;Kim et al, 2005).…”

“…Recent reports have demonstrated that DJ-1 protein protects against neuronal cell death resulting from 6-OHDA-induced ROS. After exposure to dopaminergic neurotoxins including rotenone and 6-OHDA, intracellular ROS levels were inversely correlated with DJ-1 expression levels, suggesting that DJ-1 may mitigate 6-OHDA-induced oxidative stress and help protect cells against oxidative stress (Menzies et al, 2005;Xu et al, 2005;Zhou et al, 2006).…”

“…It is highly conserved from human to Escherichia coli and is localized in the cytoplasm, nucleus, and mitochondria (Bonifati et al, 2003;Gupta et al, 2008;Lee et al, 2003;Wilson et al, 2004). This protein has multiple functions including antioxidant activity, chaperonelike properties, and transcriptional regulation (Menzies et al, 2005;Xu et al, 2005;Zhou et al, 2006). In addition, it is well known that the loss of the DJ-1 function by oxidative stress and mutation leads to human PD pathogenesis (Bonifati et al, 2003).…”