Neuroprotective function of DJ-1 in Parkinson's disease

Abstract

Parkinson's disease (PD) is caused by dopaminergic neuronal death in the substantia nigra, resulting in a reduced level of dopamine in the striatum. Oxidative stress and mitochondrial dysfunction are thought to be major causes of neurodegeneration in PD. Although genetic and environmental factors are thought to affect the onset of PD, precise mechanisms at the molecular level have not been elucidated. The DJ-1 gene is a causative gene for familial PD (park7) and also an oncogene. DJ-1 has various functions, including transcriptional regulation, antioxidative stress reaction, and chaperone, protease, and mitochondrial regulation, and its activity is regulated by its oxidative status, especially that of cysteine 106 (C106) of DJ-1. Excess oxidation of DJ-1, which renders DJ-1 inactive, has been observed in patients with sporadic PD and Alzheimer's disease, suggesting that DJ-1 also participates in the onset and pathogenesis of sporadic PD as well as familial PD. DJ-1 is also a stress sensor and its expression is increased upon various stresses, including oxidative stress. In this review, we describe functions of DJ-1 against oxidative stress and possible roles of DJ-1 in the pathogenesis of PD.

Figure 1

Functions of DJ-1 and its related diseases. DJ-1 is a multifunctional protein. It is thought that excess activation and loss of function of DJ-1 trigger the onset of various diseases, including cancer and Parkinson's disease.

Figure 2

Cysteine oxidation and activation of DJ-1. DJ-1 contains three cysteine residues at amino acid numbers 46, 54, and 106 (C46, C54, and C106, resp.). C106 is sequentially oxidized with SOH, SO₂H, and SO₃H, and then C46 and C54 are oxidized or S-nitrosylated.

Figure 3

Posttranslational modifications on DJ-1. DJ-1 is oxidized at amino acid numbers 46, 54, and 106 (C46, C54, and C106, resp.), S-nitrosylated at C46 and C54 and sumoylated at K130.

Figure 4

Schematic model of activation of the tyrosine hydroxylase gene by DJ-1. In the absence of DJ-1, PSF binds to the promoter region spanning −2909 to −2707 of the tyrosine hydroxylase (TH) gene to repress its transcription. In the presence of DJ-1, DJ-1 binds to PSF to sequester PSF from the TH gene, resulting in replacement of the corepressor complex with a coactivator complex, thereby activating TH gene transcription.

Figure 5

Proposed model of the role of DJ-1 in the onset of Parkinson's disease. In the case of familial Parkinson's disease (PD), the DJ-1 gene is heritably mutated, giving rise to inactive DJ-1 that causes PD. In the case of sporadic PD, DJ-1 expression is induced in cells upon oxidative stress to prevent cell death. During the course of continuous oxidative stress, DJ-1 is highly oxidized, giving rise to inactive DJ-1 that causes PD.