OBJECTIVE: Loss of function mutations of Park7/DJ-1 gene increase the susceptibility of dopaminergic cells to reactive oxygen species and cause early onset familial Parkinson disease (PD). However, the mechanisms underlying dopaminergic neuron loss related to DJ-1 mutation remain undefined. Therefore, it is important to find the new mechanisms underlying the antioxidative functions of DJ-1. METHODS: DJ-1 knockdown cells and DJ-1 knockout mice were used to elucidate the mechanisms underlying the antioxidative stress of DJ-1. Preliminary study of the saliva from PD patients and controls was used to confirm our findings obtained from the above studies. RESULTS: Our experiments showed that DJ-1 interacted with Erk1/2 and was required for the nuclear translocation of Erk1/2 upon oxidative stimulation. The translocation of Erk1/2 activated Elk1 and sequentially promoted superoxide dismutase1 (SOD1) expression. The nuclear translocation of Erk1/2, the activation of Elk1, and the ensuing upregulation of SOD1 were all suppressed in DJ-1 knockdown cells and DJ-1 null mice treated with oxidative insult. Furthermore, reintroduction of SOD1 into DJ-1 knockdown cells protected them against oxidative stress. Finally, in the preliminary study, we found close correlation between the protein levels of DJ-1 and SOD1 in the saliva samples from different stages of PD patients. INTERPRETATION: Our studies suggest that DJ-1 regulates SOD1 expression through Erk1/2-Elk1 pathway in its protective response to oxidative insult.
OBJECTIVE: Loss of function mutations of Park7/DJ-1 gene increase the susceptibility of dopaminergic cells to reactive oxygen species and cause early onset familial Parkinson disease (PD). However, the mechanisms underlying dopaminergic neuron loss related to DJ-1 mutation remain undefined. Therefore, it is important to find the new mechanisms underlying the antioxidative functions of DJ-1. METHODS:DJ-1 knockdown cells and DJ-1 knockout mice were used to elucidate the mechanisms underlying the antioxidative stress of DJ-1. Preliminary study of the saliva from PDpatients and controls was used to confirm our findings obtained from the above studies. RESULTS: Our experiments showed that DJ-1 interacted with Erk1/2 and was required for the nuclear translocation of Erk1/2 upon oxidative stimulation. The translocation of Erk1/2 activated Elk1 and sequentially promoted superoxide dismutase1 (SOD1) expression. The nuclear translocation of Erk1/2, the activation of Elk1, and the ensuing upregulation of SOD1 were all suppressed in DJ-1 knockdown cells and DJ-1 null mice treated with oxidative insult. Furthermore, reintroduction of SOD1 into DJ-1 knockdown cells protected them against oxidative stress. Finally, in the preliminary study, we found close correlation between the protein levels of DJ-1 and SOD1 in the saliva samples from different stages of PDpatients. INTERPRETATION: Our studies suggest that DJ-1 regulates SOD1 expression through Erk1/2-Elk1 pathway in its protective response to oxidative insult.
Authors: Santiago Cuevas; Yanrong Zhang; Yu Yang; Crisanto Escano; Laureano Asico; John E Jones; Ines Armando; Pedro A Jose Journal: Hypertension Date: 2012-01-03 Impact factor: 10.190
Authors: Dominic J Hare; Manish Arora; Nicole L Jenkins; David I Finkelstein; Philip A Doble; Ashley I Bush Journal: Nat Rev Neurol Date: 2015-06-23 Impact factor: 42.937