DJ-1 and prevention of oxidative stress in Parkinson's disease and other age-related disorders.
ABSTRACT Mutations in the PARK7/DJ-1 gene are rare causes of autosomal-recessive hereditary Parkinson's disease. Loss-of-function mutations lead to the characteristic selective neurodegeneration of nigrostriatal dopaminergic neurons, which accounts for parkinsonian symptoms. Originally identified as an oncogene, DJ-1 is a ubiquitous redox-responsive cytoprotective protein with diverse functions. In addition to cell-autonomous neuroprotective roles, DJ-1 may act in a transcellular manner, being up-regulated in reactive astrocytes in chronic neurodegenerative diseases as well as in stroke. Thus, DJ-1, particularly in its oxidized form, has been recognized as a biomarker for cancer and neurodegenerative diseases. The crystal structure of DJ-1 has been solved, allowing detailed investigations of the redox-reactive center of DJ-1. Structure-function studies revealed that DJ-1 may become activated in the presence of reactive oxygen species, under conditions of oxidative stress, but also as part of physiological receptor-mediated signal transduction. DJ-1 regulates redox signaling kinase pathways and acts as a transcriptional regulator of antioxidative gene batteries. Therefore, DJ-1 is an important redox-reactive signaling intermediate controlling oxidative stress after ischemia, upon neuroinflammation, and during age-related neurodegenerative processes. Augmenting DJ-1 activity might provide novel approaches to treating chronic neurodegenerative illnesses such as Parkinson's disease and acute damage such as stroke.
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ABSTRACT: Oxidative stress and mitochondrial dysfunction have been linked to Parkinson's disease. DJ-1 is a recessive familial PD gene involved in antioxidative function and mitochondrial maintenance. Myricitrin, a flavanoid isolated from the root bark of Myrica cerifera, has potent antioxidative properties. In the present study, we investigated the protective effects of myricitrin against MPP(+)-induced mitochondrial dysfunction in SN4741 cells and attempted to elucidate the mechanisms underlying this protection. The results showed that incubating SN4741 cells with myricitrin significantly reduced cell death induced by the neurotoxin MPP(+). Furthermore, myricitrin protected cells from MPP(+)-induced effects on mitochondrial morphology and function. However, these protective effects were lost under DJ-1-deficient conditions. Thus, our results suggest that myricitrin alleviates MPP(+)-induced mitochondrial dysfunction and increases cell viability via DJ-1, indicating that myricitrin is a potential beneficial agent for age-related neurodegenerative diseases, particularly Parkinson's disease. Copyright © 2015. Published by Elsevier Inc.Biochemical and Biophysical Research Communications 01/2015; DOI:10.1016/j.bbrc.2015.01.060 · 2.28 Impact Factor
Non-fibrillar Amyloidogenic Protein Assemblies—Common Cytotoxins Underlying Degenerative Diseases, Edited by Farid Rahimi, Gal Bitan, 01/2012: chapter Overview of fibrillar and oligomeric assemblies of amyloidogenic proteins: pages 1-36; Springer., ISBN: 9789400727731