Role of DJ-1 in the mechanism of pathogenesis of Parkinson's disease

Abstract

DJ-1 protein has multiple specific mechanisms to protect dopaminergic neurons against neurodegeneration in Parkinson's disease. Wild type DJ-1 can acts as oxidative stress sensor and as an antioxidant. DJ-1 exhibits the properties of molecular chaperone, protease, glyoxalase, transcriptional regulator that protects mitochondria from oxidative stress. DJ-1 increases the expression of two mitochondrial uncoupling proteins (UCP 4 and UCP5), that decrease mitochondrial membrane potential and leads to the suppression of ROS production, optimizes of a number of mitochondrial functions, and is regarded as protection for the neuronal cell survival. We discuss also the stabilizing interaction of DJ-1 with the mitochondrial Bcl-xL protein, which regulates the activity of (Inositol trisphosphate receptor) IP₃R, prevents the cytochrome c release from mitochondria and inhibits the apoptosis activation. Upon oxidative stress DJ-1 is able to regulate various transcription factors including nuclear factor Nrf2, PI3K/PKB, and p53 signal pathways. Stress-activated transcription factor Nrf2 regulates the pathways to protect cells against oxidative stress and metabolic pathways initiating the NADPH and ATP production. DJ-1 induces the Nrf2 dissociation from its inhibitor Keap1 (Kelch-like ECH-associated protein 1), promoting Nrf2 nuclear translocation and binding to antioxidant response elements. DJ-1 is shown to be a co-activator of the transcription factor NF-kB. Under nitrosative stress, DJ-1 may regulate PI3K/PKB signaling through PTEN transnitrosylation, which leads to inhibition of phosphatase activity. DJ-1 has a complex modulating effect on the p53 pathway: one side DJ-1 directly binds to p53 to restore its transcriptional activity and on the other hand DJ-1 can stimulate deacylation and suppress p53 transcriptional activity. The ability of the DJ-1 to induce activation of different transcriptional factors and change redox balance protect neurons against aggregation of α-synuclein and oligomer-induced neurodegeneration.

Keywords: DJ-1; Parkinson’s disease; mitochondria; neurodegeneration; oxidative stress.

Fig. 1

Diversity of the effects of DJ-1 in cell. 1. DJ-1 is able to upregulate dopamine synthesis via direct activation of tyrosine hydroxylase (TH) and 4-dihydroxy-L-phenylalanine decarboxylase (DDC). 2. In the nucleus DJ-1 acts as a transcriptional coactivator of NF-kB and subsequent transcription of the gene encoding UCP4. UCP-induced mild uncoupling can reduce the ROS production. 3. DJ-1 prevents potentially toxic a-syn aggregation via activation of a-syn degradation by the chaperone-mediated authophagy (CMA). 4. DJ-1 stimulates endogenous antioxidant system by the activation of Nrf2. 5. DJ-1 upregulates and stabilizes Bcl-xL in mitochondria preventing apoptotis. 6. DJ-1 positively regulates p53 through Topors-mediated sumoylation. Overexpression of DJ-1 decreases the expression of Bax and inhibits apoptosis. DJ-1 also inhibits PTEN to activate PI3K/PKB (Akt) pathway

Fig. 2

ROS activated DJ-1 is able to interact with complex I and maintain its activity. In addition, DJ-1 suppresses ROS overproduction, triggering expression of the gene encoding UCP. This process is mediated by activation of IκB kinase followed by activation of the transcription factor NF-κB and expression of genes encoding UCP4, UCP5 and Bcl-xL. UCP causes a mild uncoupling of oxidative phosphorylation, suppressing the production of ROS and thereby regulating the level of ROS on the principle of negative feedback. Bcl-xL is able to control mitochondrial and reticular Ca²⁺ transport through the activation of IP3R and VDAC – the components of the MAM complex. The main role of Bcl-xL is to suppress the apoptosis. Mutations in the gene encoding DJ-1 lead to disruption of these functions. So replacing the C106A blocks the activation of DJ-1 by reactive oxygen species, and the L166P mutation provides the nuclear localization of DJ-1