Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with the degeneration of dopamine neurons of the substantia nigra pars compacta (SNpc) and the presence of intra-neuronal aggregates of α-synuclein and its post-translational products. Based on emerging reports on the association between glycated α-synuclein and PD; and the newly identified deglycase activity of DJ-1, we sought to find the relevance of deglycase activity of DJ-1 on glycation of α-synuclein and its plausible role in PD. Our results demonstrate that DJ-1 has a higher affinity towards the substrate methylglyoxal (MGO) (Km = 900 mM) as compared to its familial mutant, L166P (Km = 1900 mM). Also, CML α-sy... More
Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with the degeneration of dopamine neurons of the substantia nigra pars compacta (SNpc) and the presence of intra-neuronal aggregates of α-synuclein and its post-translational products. Based on emerging reports on the association between glycated α-synuclein and PD; and the newly identified deglycase activity of DJ-1, we sought to find the relevance of deglycase activity of DJ-1 on glycation of α-synuclein and its plausible role in PD. Our results demonstrate that DJ-1 has a higher affinity towards the substrate methylglyoxal (MGO) (Km = 900 mM) as compared to its familial mutant, L166P (Km = 1900 mM). Also, CML α-synuclein (CML-syn) served as a substrate for the deglycase activity of DJ-1. Treatment of cells with Parkinsonian mimetic, 1-methyl-4-phenylpyridinium ion (MPP+); oxidants, such as H2O2 and methylglyoxal (MGO) lead to a dose-dependent decrease in the levels of DJ-1 with a concomitant increase in CML-syn. Also, MGO induced cytosolic α-synuclein aggregates in cells which stained positive with the anti-CML antibody. Further, unilateral stereotaxic administration of MGO into the SNpc of mice induced α-synuclein aggregates and CML-syn with a concomitant reduction in the number of TH positive neurons, protein levels of TH and DJ-1 at the site of injection. Interestingly, overexpression of DJ-1 enhanced the clearance of preformed CML-syn in cells, mitigated MGO induced CML-syn and intracellular α-synuclein aggregates. Overall, the findings of our present study demonstrate that DJ-1 plays a pivotal role in the glycation and aggregation of α-synuclein. Reduced DJ-1 activity due to mutations or oxidative stress may lead to the accumulation of glycated α-synuclein and its aggregates.,Copyright © 2019 Elsevier Inc. All rights reserved.
