The progressive loss of motor control due to reduction of dopamine-producing neurons in the substantia nigra pars compacta and decreased striatal dopamine levels are the classically described features of Parkinson disease (PD). Neuronal damage also progresses to other regions of the brain, and additional nonmotor dysfunctions are common. Accumulation of environmental toxins, such as pesticides and metals, are suggested risk factors for the development of typical late onset PD, although genetic factors seem to be substantial in early onset cases. Mutations of DJ-1 are known to cause a form of recessive early onset Parkinson disease, highlighting an important functional role for DJ-1 in early disease prevention. This study identifies human DJ-1 as a metal-binding protein able to evidently bind copper as well as toxic mercury ions in vitro. The study further characterizes the cytoprotective function of DJ-1 and PD-mutated variants of DJ-1 with respect to induced metal cytotoxicity. The results show that expression of DJ-1 enhances the cells' protective mechanisms against induced metal toxicity and that this protection is lost for DJ-1 PD mutations A104T and D149A. The study also shows that oxidation site-mutated DJ-1 C106A retains its ability to protect cells. We also show that concomitant addition of dopamine exposure sensitizes cells to metal-induced cytotoxicity. We also confirm that redox-active dopamine adducts enhance metal-catalyzed oxidation of intracellular proteins in vivo by use of live cell imaging of redox-sensitive S3roGFP. The study indicates that even a small genetic alteration can sensitize cells to metal-induced cell death, a finding that may revive the interest in exogenous factors in the etiology of PD. Parkinson disease (PD)3 is the second most common neurodegenerative disease, classically described as a progressive movement disorder, and with increased prevalence in the aging population. Selective degeneration of dopamine-producing neurons in the substantia nigra pars compacta (SNpc) and depletion of striatal dopamine levels are the cardinal features of PD (1). It has been estimated that 50 -60% of the SNpc dopaminergic neurons are irreversibly lost, and about 80 -85% of the dopamine content of the striatum is depleted by the time of clinical diagnosis (2). However, there are also widespread alterations in other brain regions observed in a predominant caudal to rostral progression that may influence the development of non-motor symptoms, such as pain, sleep disorders, cognitive decline, or depression (3, 4). Because the progression of the disease is slow, but irreversible, the underlying factors resulting in cell death need to be clarified to enable new treatment strategies for the affected patients.PD etiology remains obscure and appears in most instances sporadic in nature. Environmental risk factors, including prolonged pesticide exposure and lead or manganese intoxication, have been observed to cause parkinsonian symptoms (5-8). Altered zinc, copper, and iron levels have been found specifi...

Epigenetic processes control the embryonic development into multicellular organisms and determine the functional differences of genetically identical cells and individuals. They are also involved in a variety of complex functions such as learning and memory consolidation and have been implicated in aging processes. Beyond the actual genetic information encoded in the DNA sequence, epigenetic modifications in particular DNA methylation and various histone modifications shape the chromatin into a transcriptional permissive or repressive state. DNA methylation patterns are altered by environmental conditions and can be carried forward through mitosis and meiosis. Hence, DNA methylation probably mediates complex environment-gene interactions, determines individual disease characteristics, and contributes to effects and side effects of drugs. In addition to classic monogenic epigenetic diseases, i.e., Prader-Willi and Rett syndrome, recent data point to an epigenetic component also in apparent sporadic neuro-psychiatric disorders and increasing evidence suggests a role for altered DNA methylation in Parkinson's disease. Epigenetic alterations, DNA methylation in particular, may account for the yet unexplained individual susceptibility and the variability in the course of Parkinson's disease and could provide hints toward the development of novel therapeutic targets.

DJ-1 is an oxidation sensitive protein encoded by the PARK7 gene. Mutations in PARK7 are a rare cause of familial recessive Parkinson’s disease (PD), but growing evidence suggests involvement of DJ-1 in idiopathic PD. The key clinical features of PD, rigidity and bradykinesia, result from neurotransmitter imbalance, particularly the catecholamines dopamine (DA) and noradrenaline. We report in human brain and human SH-SY5Y neuroblastoma cell lines that DJ-1 predominantly forms high molecular weight (HMW) complexes that included RNA metabolism proteins hnRNPA1 and PABP1 and the glycolysis enzyme GAPDH. In cell culture models the oxidation status of DJ-1 determined the specific complex composition. RNA sequencing indicated that oxidative changes to DJ-1 were concomitant with changes in mRNA transcripts mainly involved in catecholamine metabolism. Importantly, loss of DJ-1 function upon knock down (KD) or expression of the PD associated form L166P resulted in the absence of HMW DJ-1 complexes. In the KD model, the absence of DJ-1 complexes was accompanied by impairment in catecholamine homeostasis, with significant increases in intracellular DA and noraderenaline levels. These changes in catecholamines could be rescued by re-expression of DJ-1. This catecholamine imbalance may contribute to the particular vulnerability of dopaminergic and noradrenergic neurons to neurodegeneration in PARK7-related PD. Notably, oxidised DJ-1 was significantly decreased in idiopathic PD brain, suggesting altered complex function may also play a role in the more common sporadic form of the disease.