DJ-1 and prevention of oxidative stress in Parkinson's disease and other age-related disorders.
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.
Kahle
Philipp J
PJ
Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University Clinics Tübingen, 72076 Tübingen, Germany. philipp.kahle@uni-tuebingen.de
Waak
Jens
J
Gasser
Thomas
T
D000367:Age Factors; D000818:Animals; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071617:Protein Deglycase DJ-1; D020521:Stroke / Q000235:genetics / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1