Pathogenesis of DJ-1/PARK7-Mediated Parkinson's Disease

Abstract

Parkinson's disease (PD) is a common movement disorder associated with the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Mutations in the PD-associated gene PARK7 alter the structure and function of the encoded protein DJ-1, and the resulting autosomal recessively inherited disease increases the risk of developing PD. DJ-1 was first discovered in 1997 as an oncogene and was associated with early-onset PD in 2003. Mutations in DJ-1 account for approximately 1% of all recessively inherited early-onset PD occurrences, and the functions of the protein have been studied extensively. In healthy subjects, DJ-1 acts as an antioxidant and oxidative stress sensor in several neuroprotective mechanisms. It is also involved in mitochondrial homeostasis, regulation of apoptosis, chaperone-mediated autophagy (CMA), and dopamine homeostasis by regulating various signaling pathways, transcription factors, and molecular chaperone functions. While DJ-1 protects neurons against damaging reactive oxygen species, neurotoxins, and mutant α-synuclein, mutations in the protein may lead to inefficient neuroprotection and the progression of PD. As current therapies treat only the symptoms of PD, the development of therapies that directly inhibit oxidative stress-induced neuronal cell death is critical. DJ-1 has been proposed as a potential therapeutic target, while oxidized DJ-1 could operate as a biomarker for PD. In this paper, we review the role of DJ-1 in the pathogenesis of PD by highlighting some of its key neuroprotective functions and the consequences of its dysfunction.

Keywords: DJ-1; PARK7; Parkinson’s disease; mitochondria; neuroprotection; neurotoxicity; oxidative stress; reactive oxygen species.

Figure 1

Mutations in the PARK7 gene lead to transcription of dysfunctional DJ-1 protein. This has fatal consequences for the cells, and neurons in particular, and results in mitochondrial dysfunction, impaired autophagy, neuroinflammation, loss of the neurotransmitter dopamine, and cell death. The interplay between all these processes and factors is contributing to the pathogenesis of PD. Illustrated with BioRender.com.

Figure 2

Post-translational modifications (PTMs) of DJ-1, including oxidation at cysteine residues C46, C53, C106, sumoylation at lysin residue K130, and S-nitrosylation at cysteine residues C46 and C53. The activity of DJ-1 changes depending on the PTM. The oxidations SOH and SO₂H of C106 and sumoylation of K130 lead to an active DJ-1, whereas the oxidation to SO₃H of C106, excessive sumoylation of K130, and S-nitrosylation result in an inactive form of DJ-1. Illustrated with BioRender.com.

Figure 3

Cellular effects of the PARK7-encoded protein DJ-1. The multifunctional protein DJ-1 plays a role in many cellular systems, including (1) the endogenous antioxidant system by activating Nrf2 through dissociation from its inhibitor Keap1, (2) inhibition of reactive oxygen species (ROS) production by acting as transcriptional coactivator of NfkB and subsequent transcription of the genes encoding UCP4,5, (3) inhibition of apoptosis through upregulation and stabilization of Bcl-xL in mitochondria, (4) positive regulation of proapoptotic p53 transcriptional activity through Topors-mediated sumoylation (SUMO), leading to increased Bax expression and a-synuclein transcription, and direct repression with subsequent suppression of Bax-mediated apoptosis. DJ-1 also inhibits PTEN, activating the PI3K/Akt pathway resulting in cell survival, and inhibiting p53-induced apoptosis, (5) regulation of the activity of chaperone-mediated autophagy (CMA), LAMP2A levels, and a-synuclein aggregation, and (6) stimulation of dopamine synthesis via activation of tyrosine hydroxylase (TH) and 4-dihydroxy-L-phenylalanine decarboxylase (DDC). Furthermore, DJ-1 stimulates the expression of the dopamine transporters VMAT2 and DAT, resulting in dopamine reuptake that decreases dopamine toxicity. Illustrated with BioRender.com.

Figure 4

The PINK1/Parkin pathway in mitochondrial quality control (MQC). When the outer mitochondrial membrane (OMM) is functional, PINK1 is degraded in the cytosol. When the OMM is disrupted, PINK1 is recruited to the OMM where it accumulates, is activated, and auto-phosphorylates, thus facilitating Parkin ubiquitination (Ub) and mitophagy of the damaged mitochondrial membrane proteins. Ubiquitination by Parkin enhances mitophagy, whereas dysfunction of Parkin causes accumulation of substrates and proteins otherwise marked for degradation. DJ-1 is thought to enhance the activity of PINK1 at the OMM, thereby supporting the PINK1-dependent Parkin-mediated mitophagy, but the exact mechanism is not clear. Illustrated with BioRender.com.

Figure 5

DJ-1 regulates apoptosis by increasing miR-221 expression. DJ-1 stimulates the phosphorylation of extracellular signal-regulated kinase (ERK), thus increasing ERK pathway activity. This increases miR-221 expression, which inhibits pro-apoptotic modulators from inducing apoptosis in neurons upon oxidative stress. DJ-1 also stimulates the expression of miR-221 directly. Illustrated with BioRender.com.

Figure 6

Degradation of monomeric α-synuclein (α-syn) via chaperone-mediated autophagy (CMA). Monomeric α-syn is degraded by LAMP-2A receptors in CMA. In the presence of DJ-1, the chaperone protein c-HSC70 binds monomeric α-syn in the cytosol and transports it to the lysosomal membrane, where the complex binds to a LAMP-2A monomer. When the complex is bound, LAMP-2A forms a functional homotetrameric receptor that allows α-syn to be translocated to the lysosomal lumen where it is degraded by proteases. HSC70 is reused in the lysosome as lysosomal HSC70 (l-HSC70). When DJ-1 is absent, monomeric LAMP-2A is degraded faster, and LAMP-2A receptors do not form as often. Consequently, monomeric α-syn cannot be degraded at the lysosomal lumen and instead accumulates in the cytosol. Illustrated with BioRender.com.

Figure 7

DJ-1 regulates the synthesis of dopamine. On the left is the synthesis of dopamine from tyrosine. Tyrosine is converted to L-DOPA by tyrosine hydroxylase (TH). L-DOPA is then converted to dopamine by aromatic L-amino acid decarboxylase (AADC). On the right is an illustration of the regulatory function of DJ-1 on the promotor region of the human TH-gene. Without DJ-1 present, the co-repressor pyrimidine tract-binding protein-associated splicing factor (PSF) is sumoylated and binds to the promoter region of the TH-gene, inhibiting the expression of TH. When DJ-1 is present, the sumoylation of PSF is blocked and it cannot therefore bind the promoter region of the TH-gene, resulting in transcription of TH. Hence, DJ-1 increases expression of human TH-gene on transcriptional level, leading to higher amounts of TH for dopamine synthesis. Illustrated with BioRender.com.