DJ-1 Protects Against Dopamine Toxicity: Implications for Parkinson's Disease and Aging

Abstract

Parkinson's disease (PD) is a common age-related neurodegenerative disorder. Dopamine neurotoxicity, mediated through oxidative stress, is implicated in disease pathogenesis. The vesicular monoamine transporter-2 (VMAT2) transfers dopamine into synaptic vesicles preparing it for exocytotic release and preventing its cytoplasmic oxidation. DJ-1 mutations cause early-onset familial PD. Here, we show that DJ-1 protects dopaminergic neurons and controls the vesicular sequestration of dopamine by upregulating VMAT2. Overexpression of DJ-1 protected cells against dopamine toxicity, reduced oxidative stress, and increased VMAT2 expression and function. Reduced DJ-1 levels resulted in opposite effects. Dopamine vesicular sequestration and its release upon depolarization were dependent on DJ-1 levels. Transcriptional regulation of VMAT2 expression by DJ-1 was confirmed by chromatin immunoprecipitation assay. The results were corroborated in vivo using 6-hydroxydopamine hemiparkinsonian mouse model and transgenic DJ-1 knockout mice. Our experimental data point to a novel potential protective function of DJ-1, which could be used as a therapeutic tool.

The Role of Oxidative Stress in Parkinson's Disease

“…A number of in vitro and in vivo studies have established that over-expression of wild-type DJ-1 is protective against H 2 O 2 , 6-OHDA, rotenone or MPTP, while DJ-1 mutants lack this effect [337, 342–347]. On the other hand, knocking down DJ-1 exacerbates the cell death induced by oxidative stress, as well as in response to other insults such as endoplasmic reticulum (ER) stress, proteasome inhibition and calcium entry [342, 348, 349].…”

“…Accordingly, over-expression of DJ-1 in dopaminergic cells inhibits protein aggregation and cytotoxicity caused by alpha-synuclein [372]. DJ-1 can also increase the expression of vesicular monoamine transporter-2 (VMAT2) [347, 375]. Since VMAT2 keeps cytoplasmic dopamine levels in check by storing the transmitter in synaptic vesicles, DJ-1 decreases intracellular ROS levels and enhances the resistance of cells against dopamine toxicity.…”

“…Since VMAT2 keeps cytoplasmic dopamine levels in check by storing the transmitter in synaptic vesicles, DJ-1 decreases intracellular ROS levels and enhances the resistance of cells against dopamine toxicity. Reducing DJ-1 levels has the opposite effect [347]. Thus, DJ-1 can confer neuroprotection through up-regulating VMAT2 by enabling the rapid and efficient transport of dopamine from the cytoplasm to vesicles.…”

Recent advances in biomarkers for Parkinson’s disease focusing on biochemicals, omics and neuroimaging

“…DJ-1 gene knock-out human neuroblastoma SH-SY5Y cells were susceptible to neurotoxicity induced by 1-methyl-4-phenylpyridiniumion (MPP + ), 6-hydroxydopamine (6-OHDA) and rotenone, whereas over expression of DJ-1 reduced oxidative stress and protected neurons against dopamine toxicity [35]. Previous studies have found both higher and lower cerebrospinal fluid (CSF) DJ-1 levels in PD compared with non-PD controls ( Table 1).…”

Network modeling to identify new mechanisms and therapeutic targets for Parkinson’s disease

“…Changes in dopamine transporter function could explain symptoms that are responsive to levodopa and the slow progression of the disease, since symptoms would not necessarily be due to cell loss. DJ-1 upregulates dopamine transporter levels and protects cells from dopamine toxicity [39]. In developing models of PD, it may be important to distinguish symptoms resulting from transporter function and dopamine levels versus those resulting from neurodegeneration and loss of dopaminergic neurons.…”